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Find video protocols related to scientific articles indexed in Pubmed.
Safety Assessment of Animal- and Plant-Derived Amino Acids as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-18-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of animal- and plant-derived amino acid mixtures, which function as skin and hair conditioning agents. The safety of ?-amino acids as direct food additives has been well established, based on extensive research through acute and chronic dietary exposures and the Panel previously has reviewed the safety of individual ?-amino acids in cosmetics. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that these 21 ingredients are safe in the present practices of use and concentration as used in cosmetics.
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Amended safety assessment of hypericum perforatum-derived ingredients as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) has issued an amended safety assessment of 7 Hypericum perforatum-derived ingredients as used in cosmetics. A common name for this plant is St John wort. These ingredients function in cosmetics as skin-conditioning agents-miscellaneous and antimicrobial agents. The Panel reviewed relevant animal and human data related to the H perforatum-derived ingredients. Because formulators may use more than 1 botanical ingredient in a formulation, caution was urged to avoid levels of toxicological concern for constituent chemicals and impurities. The Panel concluded that H perforatum-derived ingredients were safe as cosmetic ingredients in the practices of use and concentration as described in this safety assessment.
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Safety Assessment of Vitis vinifera (Grape)-Derived Ingredients as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 24 Vitis vinifera (grape)-derived ingredients and found them safe in the present practices of use and concentration in cosmetics. These ingredients function in cosmetics mostly as skin-conditioning agents, but some function as antioxidants, flavoring agents, and/or colorants. The Panel reviewed the available animal and clinical data to determine the safety of these ingredients. Additionally, some constituents of grapes have been assessed previously for safety as cosmetic ingredients by the Panel, and others are compounds that have been discussed in previous Panel safety assessments.
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Safety assessment of modified terephthalate polymers as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The safety of 6 modified terephthalate polymers as cosmetic ingredients was assessed. These ingredients mostly function as exfoliants, bulking agents, hair fixatives, and viscosity-increasing agents-nonaqueous. Polyethylene terephthalate (PET) is used in leave-on products up to 100% and in rinse-off products up to 2%. The Cosmetic Ingredient Review Expert Panel (Panel) considered that the PET used in cosmetics is chemically equivalent to that used in medical devices. The Panel determined that the Food and Drug Administration's determination of safety of PET in several medical devices, which included human and animal safety data, can be used as the basis for the determination of safety of PET and related polymers used in cosmetics. Use studies of cosmetic eye products that contain PET demonstrated no ocular irritation or dermal sensitization. The Panel concluded that modified terephthalate polymers were safe as cosmetic ingredients in the practices of use and concentration described in this safety assessment.
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Safety assessment of 6-hydroxyindole as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 10-10-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6-hydroxyindole, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that 6-hydroxyindole is safe for use in oxidative hair dye formulations.
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Atorvastatin Induces Bile Acid-synthetic Enzyme Cyp7a1 by Suppressing FXR Signaling in Both Liver and Intestine in Mice.
J. Lipid Res.
PUBLISHED: 10-04-2014
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Statins are effective cholesterol-lowering drugs to treat cardiovascular diseases. Bile acids (BAs), the end products of cholesterol metabolism in liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day p.o.) for one week, followed by BA profiling by UPLC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BAs in the intestine. Surprisingly, atorvastatin did not alter total BAs in serum or liver. Atorvastatin increased the ratio of 12?-OH/non-12?-OH BAs. Messenger RNA assays indicate that atorvastatin increased the mRNAs of the BA-synthetic enzymes Cyp7a1 (over 10-fold) and Cyp27a1, BA uptake transporters Ntcp and Oatp1b2, and BA efflux transporter Mrp2 in liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor FXR target genes, namely SHP (liver) and Fgf15 (ileum). Furthermore, atorvastatin increased the mRNAs of the cation uptake transporter Oct1 and cholesterol efflux transporters Abcg5 and Abcg8 in liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both liver and intestine.
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Safety Assessment of PEGylated Oils as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 08-27-2014
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PEGylated oil is a terminology used to describe cosmetic ingredients that are the etherification and esterification products of glycerides and fatty acids with ethylene oxide. The Cosmetic Ingredient Review Expert Panel (Panel) considered the safety of PEGylated oils, which function primarily as surfactants in cosmetic products. The Panel reviewed relevant animal and human data provided in this safety assessment and concluded that the 130 chemically related PEGylated oils were safe as cosmetic ingredients in the present practices of use and concentration when formulated to be nonirritating.
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Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2.
Toxicol. Lett.
PUBLISHED: 08-26-2014
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This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5mg/kg, sc for 4 days) and the genetic Nrf2 activation (Nrf2-null, wild-type, and Keap1-HKO mice) to examine the role of Nrf2 in protection against phalloidin hepatotoxicity. Mice were given phalloidin (1.5mg/kg, ip for 8h) to examine liver injury and the expression of toxicity-related genes. Phalloidin increased serum enzyme activities and caused extensive hepatic hemorrhage and necrosis in Nrf2-null and wild-type mice, but less injury was seen in Keap1-HKO mice and OA-pretreated mice. Phalloidin increased the expression of neutrophil-specific chemokine mKC and MIP-2 in Nrf2-null and WT mice, but such increases were attenuated in Keap1-HKO and OA-pretreated mice. Phalloidin increased, while Nrf2 activation attenuated, the expression of genes involved in acute-phase response (Ho-1) and DNA-damage response genes (Gadd45 and Chop10). Phalloidin is taken up by hepatocytes through Oatp1b2, but there was no difference in basal and phalloidin-induced Oatp1b2 expression among Nrf2-null, wild-type, and Keap1-HKO mice. In contrast, OA decreased phalloidin-induced Oatp1b2. Phalloidin activated MAPK signaling (p-JNK), which was attenuated by activation of Nrf2. In conclusion, this study demonstrates that protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2.
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Adaptive hepatic and intestinal alterations in mice after deletion of NADPH-cytochrome P450 Oxidoreductase (Cpr) in hepatocytes.
Drug Metab. Dispos.
PUBLISHED: 08-21-2014
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Cytochrome P450 enzymes (P450) play an important role in first-pass metabolism in both the intestine and liver. NADPH-cytochrome P450 oxidoreductase (Cpr) is an essential electron transfer protein required for microsomal P450 activity. Mice with conditional knockout of Cpr in hepatocytes develop normally and survive even with complete loss of liver microsomal P450 activity. Our current studies were performed to determine whether alternative drug-metabolizing pathways increase in an attempt to maintain whole-body homeostasis. In addition to the liver, Cpr is mainly expressed in tissues such as lung, kidney, and gastrointestinal tract. In livers of H-Cpr-null mice, there is a marked increase in mRNA expression of phase I enzymes (Aldh1a1, 1a7, 3a2; Ces1b2, 2a6, and 2a12), antioxidant enzymes (Ho-1, Nqo1, and epoxide hydrolase), phase II enzymes (Ugt1a9; Gsta1/2, m3, m4, m6, t1, and t3; and Sult1a1 and 1d1), and drug transporters (Oatp1a4, Oct3, Mate1, Mdr1a, and Mrp3 and 4). In addition, glucuronide-conjugated bilirubin concentrations are doubled in serum of H-Cpr-null mice. Both constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein in nuclei are higher in the livers of H-Cpr-null mice, indicating that CAR and Nrf2 are activated. In the small intestine of H-Cpr-null mice, mRNA expression of Cyp3a11 and Mdr1a, two genes critical for intestinal first-pass metabolism, are markedly up-regulated. In addition, nutrient (Pept1) and cholesterol (Npc1l1) transporters are induced in the small intestine of H-Cpr-null mice. In conclusion, in H-Cpr-null mice, adaptive regulation of alternative detoxification genes in liver and small intestine appear to partially compensate for the loss of microsomal P450 function in liver.
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Potency of individual bile acids to regulate bile Acid synthesis and transport genes in primary human hepatocyte cultures.
Toxicol. Sci.
PUBLISHED: 07-23-2014
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Bile acids (BAs) are known to regulate their own homeostasis, but the potency of individual bile acids is not known. This study examined the effects of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) on expression of BA synthesis and transport genes in human primary hepatocyte cultures. Hepatocytes were treated with the individual BAs at 10, 30, and 100?M for 48 h, and RNA was extracted for real-time PCR analysis. For the classic pathway of BA synthesis, BAs except for UDCA markedly suppressed CYP7A1 (70-95%), the rate-limiting enzyme of bile acid synthesis, but only moderately (35%) down-regulated CYP8B1 at a high concentration of 100?M. BAs had minimal effects on mRNA of two enzymes of the alternative pathway of BA synthesis, namely CYP27A1 and CYP7B1. BAs increased the two major target genes of the farnesoid X receptor (FXR), namely the small heterodimer partner (SHP) by fourfold, and markedly induced fibroblast growth factor 19 (FGF19) over 100-fold. The BA uptake transporter Na(+)-taurocholate co-transporting polypeptide was unaffected, whereas the efflux transporter bile salt export pump was increased 15-fold and OST?/? were increased 10-100-fold by BAs. The expression of the organic anion transporting polypeptide 1B3 (OATP1B3; sixfold), ATP-binding cassette (ABC) transporter G5 (ABCG5; sixfold), multidrug associated protein-2 (MRP2; twofold), and MRP3 (threefold) were also increased, albeit to lesser degrees. In general, CDCA was the most potent and effective BA in regulating these genes important for BA homeostasis, whereas DCA and CA were intermediate, LCA the least, and UDCA ineffective.
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Decreased bile-acid synthesis in livers of hepatocyte-conditional NADPH-cytochrome P450 reductase-null mice results in increased bile acids in serum.
J. Pharmacol. Exp. Ther.
PUBLISHED: 07-17-2014
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NADPH-cytochrome P450 reductase (Cpr) is essential for the function of microsomal cytochrome P450 monooxygenases (P450), including those P450s involved in bile acid (BA) synthesis. Mice with hepatocyte-specific deletion of NADPH-cytochrome P450 reductase (H-Cpr-null) have been engineered to understand the in vivo function of hepatic P450s in the metabolism of xenobiotics and endogenous compounds. However, the impact of hepatic Cpr on BA homeostasis is not clear. The present study revealed that H-Cpr-null mice had a 60% decrease in total BA concentration in liver, whereas the total BA concentration in serum was almost doubled. The decreased level of cholic acid (CA) in both serum and livers of H-Cpr-null mice is likely due to diminished enzyme activity of Cyp8b1 that is essential for CA biosynthesis. Feedback mechanisms responsible for the reduced liver BA concentrations and/or increased serum BA concentrations in H-Cpr-null mice included the following: 1) enhanced alternative BA synthesis pathway, as evidenced by the fact that classic BA synthesis is diminished but chenodeoxycholic acid still increases in both serum and livers of H-Cpr-null mice; 2) inhibition of farnesoid X receptor activation, which increased the mRNA of Cyp7a1 and 8b1; 3) induction of intestinal BA transporters to facilitate BA absorption from the intestine to the circulation; 4) induction of hepatic multidrug resistance-associated protein transporters to increase BA efflux from the liver to blood; and 5) increased generation of secondary BAs. In summary, the present study reveals an important contribution of the alternative BA synthesis pathway and BA transporters in regulating BA concentrations in H-Cpr-null mice.
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Safety Assessment of Dimethicone Crosspolymers as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 62 dimethicone crosspolymer ingredients as used in cosmetics. These ingredients function mostly as absorbents, bulking agents, film formers, hair-conditioning agents, emollient skin-conditioning agents, slip modifiers, surface modifiers, and nonaqueous viscosity-increasing agents. The Panel reviewed available animal and human data related to these polymers and addressed the issue of residual monomers. The Panel concluded that these dimethicone crosspolymer ingredients are safe in the practices of use and concentration as given in this safety assessment.
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Safety Assessment of Chlorphenesin as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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Chlorphenesin functions as a biocide in cosmetics and is used at concentrations up to 0.32% in rinse-off products and up to 0.3% in leave-on products. The Cosmetic Ingredient Review Expert Panel (Panel) noted that chlorphenesin was well absorbed when applied to the skin of rats; however, any safety concern was minimized because available data demonstrated an absence of toxicity. The Panel concluded that chlorphenesin is safe in the present practices of use and concentration.
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Safety Assessment of Cucumis sativus (Cucumber)-Derived Ingredients as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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The CIR Expert Panel assessed the safety of 6 Cucumis sativus (cucumber)-derived ingredients and found them safe in cosmetic formulations in the present practices of use and concentration. These ingredients are reported to function in cosmetics as skin-conditioning agents. Cucumber is a commonly consumed food with no history of significant adverse effects, suggesting that its ingredients should not pose any major safety issues following oral exposure. This assessment focused on the dermal exposure to the low concentrations of these ingredients as used in cosmetics. Some of the constituents of cucumbers have been assessed previously for safe use as cosmetic ingredients.
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Safety Assessment of Citric Acid, Inorganic Citrate Salts, and Alkyl Citrate Esters as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-28-2014
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The CIR Expert Panel (Panel) assessed the safety of citric acid, 12 inorganic citrate salts, and 20 alkyl citrate esters as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration. Citric acid is reported to function as a pH adjuster, chelating agent, or fragrance ingredient. Some of the salts are also reported to function as chelating agents, and a number of the citrates are reported to function as skin-conditioning agents but other functions are also reported. The Panel reviewed available animal and clinical data, but because citric acid, calcium citrate, ferric citrate, manganese citrate, potassium citrate, sodium citrate, diammonium citrate, isopropyl citrate, stearyl citrate, and triethyl citrate are generally recognized as safe direct food additives, dermal exposure was the focus for these ingredients in this cosmetic ingredient safety assessment.
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H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice.
Am. J. Physiol. Gastrointest. Liver Physiol.
PUBLISHED: 05-22-2014
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We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)-/- mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE-/- mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.
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Synergistic interaction between genetics and disease on pravastatin disposition.
J. Hepatol.
PUBLISHED: 01-31-2014
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A genome wide association study and multiple pharmacogenetic studies have implicated the hepatic uptake transporter organic anion transporting polypeptide-1B1 (OATP1B1) in the pharmacokinetics and musculoskeletal toxicity of statin drugs. Other OATP uptake transporters can participate in the transport of pravastatin, partially compensating for the loss of OATP1B1 in patients carrying the polymorphism. Non-alcoholic steatohepatitis (NASH) in humans and in a diet-induced rodent model alter the expression of multiple OATP transporters.
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Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).
Toxicol. Appl. Pharmacol.
PUBLISHED: 01-24-2014
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The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200?g/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.
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Nrf2 protects against furosemide-induced hepatotoxicity.
Toxicology
PUBLISHED: 01-17-2014
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Furosemide is a diuretic drug, but its reactive intermediates lead to acute liver injury in mice. Given the essential role of Nrf2 as a cellular defense regulator, we investigated whether Nrf2 would protect against furosemide-induced liver injury using the Nrf2 "gene-dose response" mouse model (Nrf2-null with Nrf2 knock-out, wild-type with normal expression of Nrf2, Keap1-KD with enhanced Nrf2 activation and Keap1-HKO mice with maximum Nrf2 activation). Twenty-four hours after furosemide administration (250mg/kg, i.p.), serum ALT activities and histopathological analysis indicated severe hepatotoxicity in Nrf2-null and WT mice, but significantly less in the Nrf2-overexpressing Keap1-KD and Keap1-HKO mice. Furosemide increased the mRNA of genes involved in the acute phase response (hemeoxygenase-1 and metallothionein-1), ER stress (C/Ebp-homologous protein and Growth arrest and DNA-damage-inducible protein), inflammatory cytokine (interleukin 1 beta), chemokines (macrophage inflammatory protein 2 and mouse keratinocyte-derived chemokine), as well as apoptosis (early growth response factor and BCL2-associated X protein) in livers of Nrf2-null and wild-type mice, but these genes increased less in mice with more Nrf2. The two genotypes of over-expressed Nrf2 mice had increased expression of the Nrf2 target genes Gclm, Gclc and Nqo1 prior to furosemide administration, and the expressions of these genes were increased further after furosemide administration. Thus, our findings provide strong evidence that over-expression of Nrf2 in Keap1-KD and Keap1-HKO mice and the increases in mRNA of a number of genes involved in anti-oxidative stress, anti-inflammation, anti-ER stress and anti-apoptosis protect against furosemide-induced hepatotoxicity.
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Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice.
Toxicol. Appl. Pharmacol.
PUBLISHED: 01-10-2014
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Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin+imipenem and cephalothin+neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profiles and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin+imipenem but stimulated by cephalothin+neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism.
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Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing.
PLoS ONE
PUBLISHED: 01-01-2014
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The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n?=?3/age). The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5-Day 5 (perinatal-enriched), Day 10-Day 20 (pre-weaning-enriched), and Day 25-Day 60 (adolescence/adulthood-enriched). Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid ?-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal ?-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty acids-like 3. These data shed new light on the ontogeny of homeostatic regulation of hepatic energy metabolism, which could ultimately provide new therapeutic targets for metabolic diseases.
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Overexpression of Nrf2 protects against microcystin-induced hepatotoxicity in mice.
PLoS ONE
PUBLISHED: 01-01-2014
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Oxidative stress and glutathione (GSH) depletion are implicated in mycocystin hepatotoxicity. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in microcystin-induced liver injury, Nrf2-null, wild-type, and Keap1-hepatocyte knockout (Keap1-HKO) mice were treated with microcystin (50 ?g/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Microcystin increased serum alanine aminotransferase and aspartate aminotransferase activities, and caused extensive inflammation and necrosis in Nrf2-null and wild-type mice, but not in Keap1-HKO mice. Oxidative stress and inflammation are implicated in microcystin-induced hepatotoxicity, as evidenced by increased lipid peroxidation and increased expression of pro-inflammatory genes, such as neutrophil-specific chemokines mKC and MIP-2, and pro-inflammatory cytokines IL-1? and IL-6. The increased expression of these pro-inflammatory genes was attenuated in Keap1-HKO mice. Nrf2 and Nqo1 mRNA and protein were higher in Keap1-HKO mice at constitutive levels and after microcystin. To further investigate the mechanism of the protection, hepatic GSH and the mRNA of GSH-related enzymes were determined. Microcystin markedly depleted liver GSH by 60-70% in Nrf2 and WT mice but only 35% in Keap1-HKO mice. The mRNAs of GSH conjugation and peroxide reduction enzymes, such as Gst?1, Gst?4, Gst?, and Gpx2 were higher in livers of Keap1-HKO mice, together with higher expression of the rate-limiting enzyme for GSH synthesis (Gclc). Organic anion transport polypeptides were increased by microcystin with the most increase in Keap1-HKO mice. In conclusion, this study demonstrates that higher basal levels of Nrf2 and GSH-related genes in Keap1-HKO mice prevented microcystin-induced oxidative stress and liver injury.
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Effect of diet on expression of genes involved in lipid metabolism, oxidative stress, and inflammation in mouse liver-insights into mechanisms of hepatic steatosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Nutritional intake is a fundamental determinant of health. Many studies have correlated excess caloric intake, as well as a high ratio of n-6:n-3 fatty acids, with detrimental health outcomes, such as the metabolic syndrome. In contrast, low-calorie diets have beneficial health effects. Despite these associations, our understanding of the causal relationship between diet and health remains largely elusive. The present study examined the molecular changes elicited by nine diets with varying fat, sugar, cholesterol, omega-3 fatty acids, omega-6 fatty acids, and calories in C57BL/6 male mice. Microarray analyses were conducted on liver samples from three mice per diet and detected 20,449 genes of which 3,734 were responsive to changes in dietary components. Principal component analysis showed that diet restriction correlated the least with the other diets and also affected more genes than any other diet. Interestingly, Gene Set Enrichment Analysis (GSEA) identified gene sets involved in glutathione metabolism, immune response, fatty acid metabolism, cholesterol metabolism, ABC transporters, and oxidative phosphorylation as being highly responsive to changes in diet composition. On the gene level, this study reveals novel findings such as the induction of the drug efflux pump Abcb1a (p-glycoprotein) by diet restriction and an atherogenic diet, as well as the suppression of the rate limiting step of bile acid synthesis, Cyp7a1, by a high fructose diet. This study provides considerable insight into the molecular changes incurred by a variety of diets and furthers our understanding of the causal relationships between diet and health.
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Amended safety assessment of formaldehyde and methylene glycol as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-17-2013
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Formaldehyde and methylene glycol may be used safely in cosmetics if established limits are not exceeded and are safe for use in nail hardeners in the present practices of use and concentration, which include instructions to avoid skin contact. In hair-smoothing products, however, in the present practices of use and concentration, formaldehyde and methylene glycol are unsafe. Methylene glycol is continuously converted to formaldehyde, and vice versa, even at equilibrium, which can be easily shifted by heating, drying, and other conditions to increase the amount of formaldehyde. This rapid, reversible formaldehyde/methylene glycol equilibrium is distinguished from the slow, irreversible release of formaldehyde resulting from the so-called formaldehyde releaser preservatives, which are not addressed in this safety assessment (formaldehyde releasers may continue to be safely used in cosmetics at the levels established in their individual Cosmetic Ingredient Review safety assessments).
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Safety Assessment of ?-Amino Acids as Used in Cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-17-2013
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of ?-amino acids, which function primarily as hair- and skin-conditioning agents in cosmetic products. The safety of ?-amino acids as direct food additives has been well established based on extensive research through acute and chronic dietary exposures. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that ?-amino acids were safe as cosmetic ingredients in the practices of use and concentration of this safety assessment.
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Safety assessment of ammonium hectorites as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-17-2013
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 4 ammonium hectorite compounds used in cosmetics: disteardimonium hectorite, dihydrogenated tallow benzylmonium hectorite, stearalkonium hectorite, and quaternium-18 hectorite. These ingredients function in cosmetics mainly as nonsurfactant suspending agents. The Panel reviewed available animal and human data and concluded that these ammonium hectorite compounds were safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment.
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Screening of Natural Compounds as Activators of the Keap1-Nrf2 Pathway.
Planta Med.
PUBLISHED: 12-05-2013
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Nuclear factor erythroid 2-related factor 2 is a master regulator that promotes transcription of cytoprotective genes in response to oxidative/electrophilic stress. A large number of natural dietary compounds are thought to protect against oxidative stress, and a few have been reported to induce genes involved in antioxidant defense through activating nuclear factor erythroid 2-related factor 2. Therefore, a library of 54 natural compounds were collected to determine whether they are nuclear factor erythroid 2-related factor 2 activators and to compare their efficacy and potency to activate nuclear factor erythroid 2-related factor 2. The assay utilized AREc32 cells that contain a luciferase gene under the control of antioxidant response element promoters. Each natural compound was tested at 13 concentrations between 0.02 and 30?µM. Known nuclear factor erythroid 2-related factor 2 activators tert-butylhydroquinone and 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide were used as positive controls in parallel with the natural compounds. Among the 54 tested natural compounds, andrographolide had the highest efficacy, followed by trans-chalcone, sulforaphane, curcumin, flavone, kahweol, and carnosol, all of which had better efficacy than tert-butylhydroquinone. Among the compounds tested, 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide was the most potent, having an EC50 of 0.41?µM. Seven of the natural compounds, namely andrographolide, trans-chalcone, sulforaphane, curcumin, flavone, kahweol, and cafestol had lower EC50 values than tert-butylhydroquinone but higher than 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide. The present study provides insights into which natural compounds activate the Keap1-nuclear factor erythroid 2-related factor 2 pathway and thus might be useful for detoxifying oxidative/electrophilic stress.
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Safety assessment of borosilicate glasses as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of calcium sodium borosilicate, calcium aluminum borosilicate, calcium titanium borosilicate, silver borosilicate, and zinc borosilicate as used in cosmetics. These borosilicate glasses function mostly as bulking agents. Available animal and human data were considered along with data from a previous safety assessment of magnesium silicates. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. Data submitted on calcium borosilicate, which is not a cosmetic ingredient, are also included as additional support for the safety of borosilicate glass ingredients. The Panel concluded that borosilicate glasses are safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment.
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Safety assessment of alkyl glyceryl ethers as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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Alkyl glyceryl ethers function mostly as skin-conditioning agents in cosmetic products applied to the skin and hair. The Cosmetic Ingredient Review expert panel reviewed the available animal toxicity and clinical data, including the low dermal absorption, and concluded that the alkyl glyceryl ethers are safe in the present practices of use and concentration described in this safety assessment.
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Safety assessment of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review Expert Panel assessed the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics, finding that these ingredients are safe in cosmetic formulations in the present practices of use and concentration. Both ingredients are lanolin substitutes and are reported to function in cosmetics as skin-conditioning agents--emollients. The Panel reviewed available animal and clinical data in making its determination of safety.
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Safety assessment of lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review Expert Panel assessed the safety of lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate as used in cosmetics. These ingredients function in cosmetics as hair-conditioning agents and surfactant-cleansing agents. The Panel reviewed relevant animal and human data related to the safety of these ingredients in cosmetics. The Panel concluded that lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate are safe as cosmetic ingredients in the present practices of use and concentration.
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Safety assessment of decyl glucoside and other alkyl glucosides as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-01-2013
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The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 19 alkyl glucosides as used in cosmetics and concluded that these ingredients are safe in the present practices of use and concentration when formulated to be nonirritating. Most of these ingredients function as surfactants in cosmetics, but some have additional functions as skin-conditioning agents, hair-conditioning agents, or emulsion stabilizers. The Panel reviewed the available animal and clinical data on these ingredients. Since glucoside hydrolases in human skin are likely to break down these ingredients to release their respective fatty acids and glucose, the Panel also reviewed CIR reports on the safety of fatty alcohols and were able to extrapolate data from those previous reports to support safety.
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Role of CYP3A in isoniazid metabolism in vivo.
Drug Metab. Pharmacokinet.
PUBLISHED: 10-29-2013
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  Isoniazid (INH), a first-line drug for tuberculosis control, frequently causes liver injury. Multiple previous reports suggest that CYP3A is involved in INH metabolism, bioactivation and hepatotoxicity, although direct evidence is unavailable. In the current study, wild-type and Cyp3a-null mice were used to determine the potential role of Cyp3a in INH metabolism in vivo. Compared to wild-type mice, there were no significant differences in the pharmacokinetic profiles of INH and acetyl-isoniazid in Cyp3a-null mice after an oral administration of 50 mg/kg INH. With the same treatment, distribution of INH and its major metabolites was similar in the liver of wild-type and Cyp3a-null mice. A reactive metabolite of INH was trapped by N-?-acetyl-L-lysine in mouse liver microsomes, but Cyp3a does not contribute to this bioactivation pathway. In addition, no liver injury was observed in wild-type and Cyp3a-null mice treated with 60 or 120 mg/kg INH. In summary, Cyp3a has no effect on systemic pharmacokinetics of INH in mice. Further studies are needed to determine whether and how exactly CYP3A is involved in INH bioactivation and hepatotoxicity.
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Learning to Program the Liver.
Annu. Rev. Pharmacol. Toxicol.
PUBLISHED: 10-16-2013
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Half a century ago, people were learning to program computers. Similarly, we have been trying to learn how to program the liver to protect us from chemicals. We have given various chemicals that activate transcription factors such as the nuclear receptors: These ligand-activated nuclear receptors enter the nucleus of liver cells (hepatocytes) and bind to their specific motifs in DNA to increase the transcription of various genes that protect against chemical-induced injury. Several examples from our laboratory are given to demonstrate this detoxification process: (a) a steroid chemical that increases the expression of a hepatic transporter to enhance the elimination of other chemicals and thus decrease their toxicity, (b) a metal that decreases its own toxicity by increasing the production of a protein to which it binds, and (c) an herbal chemical that activates a transcription factor that serves as a sensor of oxidative stress and electrophiles to protect against cytotoxicity by increasing the expression of numerous antioxidant proteins. In addition, at the present time, we are investigating which bile acids that are synthesized in the liver and altered by bacteria in the intestine may be used to alter the programming of the liver, as well as how the liver reprograms itself after birth in the transition from a hematopoietic organ to one that decreases the toxicity of chemicals. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 54 is January 06, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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RNA-sequencing quantification of hepatic ontogeny of phase-I enzymes in mice.
Drug Metab. Dispos.
PUBLISHED: 09-30-2013
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Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.
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Increased bile acids in enterohepatic circulation by short-term calorie restriction in male mice.
Toxicol. Appl. Pharmacol.
PUBLISHED: 08-02-2013
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Previous studies showed glucose and insulin signaling can regulate bile acid (BA) metabolism during fasting or feeding. However, limited knowledge is available on the effect of calorie restriction (CR), a well-known anti-aging intervention, on BA homeostasis. To address this, the present study utilized a "dose-response" model of CR, where male C57BL/6 mice were fed 0, 15, 30, or 40% CR diets for one month, followed by BA profiling in various compartments of the enterohepatic circulation by UPLC-MS/MS technique. This study showed that 40% CR increased the BA pool size (162%) as well as total BAs in serum, gallbladder, and small intestinal contents. In addition, CR "dose-dependently" increased the concentrations of tauro-cholic acid (TCA) and many secondary BAs (produced by intestinal bacteria) in serum, such as tauro-deoxycholic acid (TDCA), DCA, lithocholic acid, ?-muricholic acid (?MCA), and hyodeoxycholic acid. Notably, 40% CR increased TDCA by over 1000% (serum, liver, and gallbladder). Interestingly, 40% CR increased the proportion of 12?-hydroxylated BAs (CA and DCA), which correlated with improved glucose tolerance and lipid parameters. The CR-induced increase in BAs correlated with increased expression of BA-synthetic (Cyp7a1) and conjugating enzymes (BAL), and the ileal BA-binding protein (Ibabp). These results suggest that CR increases BAs in male mice possibly through orchestrated increases in BA synthesis and conjugation in liver as well as intracellular transport in ileum.
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Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice.
Toxicol. Appl. Pharmacol.
PUBLISHED: 08-01-2013
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Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver.
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Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice.
Toxicol. Appl. Pharmacol.
PUBLISHED: 06-19-2013
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Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ost?). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPAR? along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential.
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Hormonal regulation of Cyp4a isoforms in mouse liver and kidney.
Xenobiotica
PUBLISHED: 05-31-2013
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Mouse Cyp4a subfamily, including Cyp4a10, Cyp4a12a, Cyp4a12b and Cyp4a14, demonstrate a gender- and strain-specific expression in liver and kidney. In C57BL/6 mouse liver and kidney, Cyp4a12a and 4a12b are male-predominant, whereas Cyp4a14 is female-predominant. Cyp4a10 is female-predominant in liver, but shows no gender difference in kidney. The present study was aimed to determine whether sex hormones and/or growth hormone (GH) secretion patterns are responsible for the gender-specific Cyp4a expression in C57BL/6 mice. Gonadectomized mice, GH-releasing hormone receptor-deficient little (lit/lit) mice and hypophysectomized mice were used with replacement of sex hormones or GH in male or female secretion patterns. Both androgens and male-pattern GH regulated the gender-divergent Cyp4a10, 4a12a and 4a12b in liver, whereas androgens played an exclusive role in regulating Cyp4a10 and 4a12a in kidney. In contrast, Cyp4a12b was increased by male-pattern GH but not androgens in kidney. The female-predominant Cyp4a14 in liver and kidney was due to a combined effect of male-pattern GH and androgens. In addition, estrogens played a minor role in regulation of Cyp4a isoforms through an indirect pathway. In conclusion, gender-divergent Cyp4a mRNA expression in liver is caused by male-pattern GH secretion pattern and androgens, whereas in kidney, Cyp4a mRNA expression is primarily regulated by androgens.
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Safety assessment of silylates and surface-modified siloxysilicates.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate as used in cosmetics. These silylates and surface-modified siloxysilicates function in cosmetics as antifoaming agents, anticaking agents, bulking agents, binders, skin-conditioning agents--emollient, skin-conditioning agents-occlusive, slip modifiers, suspension agents--nonsurfactant, and viscosity increasing agents--nonaqueous. The Expert Panel reviewed the available animal and clinical data as well as information from a previous CIR safety assessment of amorphous silica. The CIR Expert Panel concluded that silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate are safe as used when formulated and delivered in the final product not to be irritating or sensitizing to the respiratory tract.
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Safety assessment of triethanolamine and triethanolamine-containing ingredients as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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The Cosmetic Ingredient Review Expert Panel assessed the safety of triethanolamine (TEA) and 31 related TEA-containing ingredients as used in cosmetics. The TEA is reported to function as a surfactant or pH adjuster; the related TEA-containing ingredients included in this safety assessment are reported to function as surfactants and hair- or skin-conditioning agents. The exception is TEA-sorbate, which is reported to function as a preservative. The Panel reviewed the available animal and clinical data. Although data were not available for all the ingredients, the panel relied on the information available for TEA in conjunction with previous safety assessments of components of TEA-containing ingredients. These data could be extrapolated to support the safety of all included ingredients. The panel concluded that TEA and related TEA-containing ingredients named in this report are safe as used when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds can be formed.
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Safety assessment of diethanolamides as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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Cocamide diethanolamine (DEA) and some of the other diethanolamides are mainly used as surfactant foam boosters or viscosity increasing agents in cosmetics, although a few are reported to be used as hair and skin conditioning agents, surfactant-cleansing or surfactant-emulsifying agents, or as an opacifying agent. The Cosmetic Ingredient Review (CIR) Expert Panel considered new data and information from previous CIR reports to assess the concerns about the potential for amidases in human skin to convert these diethanolamides into DEA and the corresponding fatty acids. The Expert Panel concluded that these diethanolamides are safe as used when formulated to be nonirritating and when the levels of free DEA in the diethanolamides do not exceed those considered safe by the Panel. The Panel also recommended that these ingredients not be used in cosmetic products in which N-nitroso compounds can be formed.
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Safety assessment of 2-amino-4-hydroxyethylaminoanisole and 2-amino-4-hydroxyethylaminoanisole sulfate as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 05-23-2013
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2-Amino-4-hydroxyethylaminoanisole and its salt, 2-amino-4-hydroxyethylaminoanisole sulfate, are used as coupling agents in oxidative hair dyes. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to the ingredient. The Expert Panel concluded that 2-amino-4-hydroxyethylaminoanisole and 2-amino-4-hydroxyethylaminoanisole sulfate are safe for use in oxidative hair dye formulations. The Expert Panel cautioned that these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.
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Tissue distribution, ontogeny, and chemical induction of aldo-keto reductases in mice.
Drug Metab. Dispos.
PUBLISHED: 05-09-2013
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Aldo-keto reductases (Akrs) are a conserved group of NADPH-dependent oxido-reductase enzymes. This study provides a comprehensive examination of the tissue distribution of the 16 substrate-metabolizing Akrs in mice, their expression during development, and whether they are altered by chemicals that activate distinct transcriptional factor pathways. Akr1c6, 1c14, 1c20, and 1c22 are primarily present in liver; Akr1a4, 1c18, 1c21, and 7a5 in kidney; Akr1d1 in liver and kidney; Akr1b7 in small intestine; Akr1b3 and Akr1e1 in brain; Akr1b8 in testes; Akr1c14 in ovaries; and Akrs1c12, 1c13, and 1c19 are expressed in numerous tissues. Liver expression of Akr1d1 and Akr1c is lowest during prenatal and postnatal development. However, by 20 days of age, liver Akr1d1 increases 120-fold, and Akr1c mRNAs increase as much as 5-fold (Akr1c19) to 1000-fold (Akr1c6). Treatment of mice with chemical activators of transcription factors constitutive androgen receptor (CAR), pregnane X receptor (PXR), and the nuclear factor-erythroid-2 (Nrf2) transcription factor alters liver mRNAs of Akrs. Specifically, CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) increases mRNAs of Akr1b7, Akr1c6, Akr1c19, and Akr1d1, whereas PXR activation by 5-pregnenolone-16?-carbonitrile (PCN) increases the mRNA of Akr1b7 and suppresses mRNAs of Akr1c13 and Akr1c20. The Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) induces mRNAs of Akr1c6 and Akr1c19. Moreover, Nrf2-null and Nrf2 overexpressing mice demonstrate that this induction is Nrf2-dependent.
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Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism.
Biochem. Pharmacol.
PUBLISHED: 04-08-2013
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Organic anion transporting polypeptides (human: OATPs; rodent: Oatps) were thought to have important functions in bile acid (BA) transport. Oatp1a1, 1a4, and 1b2 are the three major Oatp1 family members in rodent liver. Our previous studies have characterized the BA homeostasis in Oatp1a1-null and Oatp1b2-null mice. The present study investigated the physiological role of Oatp1a4 in BA homeostasis by using Oatp1a4-null mice. Oatp1a4 expression is female-predominant in livers of mice, and thereby it was expected that female Oatp1a4-null mice will have more prominent changes than males. Interestingly, the present study demonstrated that female Oatp1a4-null mice had no significant alterations in BA concentrations in serum or liver, though they had increased mRNA of hepatic BA efflux transporters (Mrp4 and Ost?/?) and ileal BA transporters (Asbt and Ost?/?). In contrast, male Oatp1a4-null mice showed significantly altered BA homeostasis, including increased concentrations of deoxycholic acid (DCA) in serum, liver and intestinal contents. After feeding a DCA-supplemented diet, male but not female Oatp1a4-null mice had higher concentrations of DCA in serum and livers than their WT controls. This suggested that Oatp1a4 is important for intestinal absorption of secondary BAs in male mice. Furthermore, loss of Oatp1a4 function did not decrease BA accumulation in serum or livers of bile-duct-ligated mice, suggesting that Oatp1a4 is not likely a BA uptake transporter. In summary, the present study for the first time demonstrates that Oatp1a4 does not appear to mediate the hepatic uptake of BAs, but plays an important male-predominant role in secondary BA metabolism in mice.
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Genetic activation of Nrf2 protects against fasting-induced oxidative stress in livers of mice.
PLoS ONE
PUBLISHED: 02-11-2013
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Acute fasting causes elevated oxidative stress. The current study investigated the effects of the nuclear factor erythoid 2-related factor 2 (Nrf2), the sensor of oxidative stress in cells, on energy homeostasis and liver pathophysiology during fasting. Feed was removed from mice possessing none (Nrf2-null), normal (wild-type, WT), enhanced (Keap1-knockdown, K1-KD), and maximum (hepatocyte-specific Keap1-knockout, K1-HKO) Nrf2 activity in liver for 24 h. Body weight, blood glucose, and blood lipid profiles were similar among mice with graded Nrf2 activity under either fed or fasted conditions. Fasting reduced liver size in mice expressing Nrf2, but not in Nrf2-null mice. Nrf2-null mice accumulated more non-esterified free fatty acids and triglycerides in liver after fasting than the other genotypes of mice. Fatty acids are mainly catabolized in mitochondria, and Nrf2-null mice had lower mitochondrial content in liver under control feeding conditions, which was further reduced by fasting. In contrast, mitochondrial contents in mice with enhanced Nrf2 activity were not affected by fasting. Oxidative stress, determined by staining of free radicals and quantification of malondialdehyde equivalents, was highest in Nrf2-null and lowest in K1-HKO mice after fasting. The exacerbated oxidative stress in livers of Nrf2-null mice is predicted to lead to damages to mitochondria, and therefore diminished oxidation and increased accumulation of lipids in livers of Nrf2-null mice. In summary, the Nrf2-regulated signaling pathway is critical in protecting mitochondria from oxidative stress during feed deprivation, which ensures efficient utilization of fatty acids in livers of mice.
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RNA-sequencing quantification of hepatic ontogeny and tissue distribution of mRNAs of phase II enzymes in mice.
Drug Metab. Dispos.
PUBLISHED: 02-04-2013
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Phase II conjugating enzymes play key roles in the metabolism of xenobiotics. In the present study, RNA sequencing was used to elucidate hepatic ontogeny and tissue distribution of mRNA expression of all major known Phase II enzymes, including enzymes involved in glucuronidation, sulfation, glutathione conjugation, acetylation, methylation, and amino acid conjugation, as well as enzymes for the synthesis of Phase II cosubstrates, in male C57BL/6J mice. Livers from male C57BL/6J mice were collected at 12 ages from prenatal to adulthood. Many of these Phase II enzymes were expressed at much higher levels in adult livers than in perinatal livers, such as Ugt1a6b, -2a3, -2b1, -2b5, -2b36, -3a1, and -3a2; Gsta1, -m1, -p1, -p2, and -z1; mGst1; Nat8; Comt; Nnmt; Baat; Ugdh; and Gclc. In contrast, hepatic mRNA expression of a few Phase II enzymes decreased during postnatal liver development, such as mGst2, mGst3, Gclm, and Mat2a. Hepatic expression of certain Phase II enzymes peaked during the adolescent stage, such as Ugt1a1, Sult1a1, Sult1c2, Sult1d1, Sult2as, Sult5a1, Tpmt, Glyat, Ugp2, and Mat1a. In adult mice, the total transcripts for Phase II enzymes were comparable in liver, kidney, and small intestine; however, individual Phase II enzymes displayed marked tissue specificity among the three organs. In conclusion, this study unveils for the first time developmental changes in mRNA abundance of all major known Phase II enzymes in mouse liver, as well as their tissue-specific expression in key drug-metabolizing organs. The age- and tissue-specific expression of Phase II enzymes indicate that the detoxification of xenobiotics is highly regulated by age and cell type.
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Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy.
Nat. Med.
PUBLISHED: 01-24-2013
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Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic.
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Nrf2 protection against liver injury produced by various hepatotoxicants.
Oxid Med Cell Longev
PUBLISHED: 01-14-2013
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To investigate the role of Nrf2 as a master defense against the hepatotoxicity produced by various chemicals, Nrf2-null, wild-type, Keap1-knock down (Keap1-Kd) and Keap1-hepatocyte knockout (Keap1-HKO) mice were used as a "graded Nrf2 activation" model. Mice were treated with 14 hepatotoxicants at appropriate doses, and blood and liver samples were collected thereafter (6 h to 7 days depending on the hepatotoxicant). Graded activation of Nrf2 offered a Nrf2-dependent protection against the hepatotoxicity produced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid, as evidenced by serum alanine aminotransferase (ALT) activities and by histopathology. Nrf2 activation also offered moderate protection against liver injury produced by ethanol, arsenic, bromobenzene, and allyl alcohol but had no effects on the hepatotoxicity produced by D-galactosamine/endotoxin and the Fas ligand antibody Jo-2. Graded Nrf2 activation reduced the expression of inflammatory genes (MIP-2, mKC, IL-1 ? , IL-6, and TNF ?), oxidative stress genes (Ho-1, Egr1), ER stress genes (Gadd45 and Gadd153), and genes encoding cell death (Noxa, Bax, Bad, and caspase3). Thus, this study demonstrates that Nrf2 prevents the liver from many, but not all, hepatotoxicants. The Nrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, and attenuation of oxidative stress.
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Safety assessment of xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 12-21-2011
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Xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes used in cosmetics as surfactants, hydrotropes, were reviewed in this safety assessment. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to these ingredients. The panel concluded that xylene sulfonic acid and alkyl aryl sulfonate hydrotropes are safe as cosmetic ingredients in the present practices of use and concentrations as described in this safety assessment, when formulated to be nonirritating.
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Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of pelargonic acid (nonanoic acid) and nonanoate esters.
Int. J. Toxicol.
PUBLISHED: 12-21-2011
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Pelargonic acid and its esters function as skin-conditioning agents in cosmetics. Molecular weight (mw) and octanol-water partition coefficient data suggest that dermal penetration is possible. The biohandling of branched-chain fatty acids is not the same as for straight-chain fatty acids, but the differences are not significant to the conclusion that they all are readily metabolized to nontoxic moieties. Limited data suggested that the penetration of other ingredients may be enhanced if these ingredients are present in the same formulation. These ingredients are not significant oral or dermal toxicants in animal studies. They are not reproductive/developmental toxicants or genotoxic/carcinogenic in animal studies. The available data suggested that product formulations containing these ingredients would be nonirritating and nonsensitizing to human skin, but formulators were cautioned to consider the penetration enhancement potential. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that these ingredients are safe in the present practices of use and concentration.
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Safety assessment of cyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, and cycloheptasiloxane.
Int. J. Toxicol.
PUBLISHED: 12-21-2011
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Cyclomethicone (mixture) and the specific chain length cyclic siloxanes (n = 4-7) reviewed in this safety assessment are cyclic dimethyl polysiloxane compounds. These ingredients have the skin/hair conditioning agent function in common. Minimal percutaneous absorption was associated with these ingredients and the available data do not suggest skin irritation or sensitization potential. Also, it is not likely that dermal exposure to these ingredients from cosmetics would cause significant systemic exposure. The Cosmetic Ingredient Review Expert Panel concluded that these ingredients are safe in the present practices of use and concentration.
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Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity.
J. Biol. Chem.
PUBLISHED: 12-05-2011
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Bile acids facilitate postprandial absorption of nutrients. Bile acids also activate the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5 and play a major role in regulating lipid, glucose, and energy metabolism. Transgenic expression of cholesterol 7?-hydroxylase (CYP7A1) prevented high fat diet-induced diabetes and obesity in mice. In this study, we investigated the nutrient effects on bile acid synthesis. Refeeding of a chow diet to fasted mice increased CYP7A1 expression, bile acid pool size, and serum bile acids in wild type and humanized CYP7A1-transgenic mice. Chromatin immunoprecipitation assays showed that glucose increased histone acetylation and decreased histone methylation on the CYP7A1 gene promoter. Refeeding also induced CYP7A1 in fxr-deficient mice, indicating that FXR signaling did not play a role in postprandial regulation of bile acid synthesis. In streptozocin-induced type I diabetic mice and genetically obese type II diabetic ob/ob mice, hyperglycemia increased histone acetylation status on the CYP7A1 gene promoter, leading to elevated basal Cyp7a1 expression and an enlarged bile acid pool with altered bile acid composition. However, refeeding did not further increase CYP7A1 expression in diabetic mice. In summary, this study demonstrates that glucose and insulin are major postprandial factors that induce CYP7A1 gene expression and bile acid synthesis. Glucose induces CYP7A1 gene expression mainly by epigenetic mechanisms. In diabetic mice, CYP7A1 chromatin is hyperacetylated, and fasting to refeeding response is impaired and may exacerbate metabolic disorders in diabetes.
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Final report of the Amended Safety Assessment of PVM/MA copolymer and its related salts and esters as used in cosmetics.
Int. J. Toxicol.
PUBLISHED: 11-10-2011
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Polyvinyl methyl ether/maleic acid (PVM/MA) copolymer, and its related salts and esters, are used in cosmetics, mainly as binders, film formers, and hair fixatives. Animal and human data relevant to the use of these ingredients in cosmetic products were reviewed by the CIR Expert Panel. The Panel concluded that these ingredients are safe for use in cosmetic products.
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Tissue distribution and gender-divergent expression of 78 cytochrome P450 mRNAs in mice.
Toxicol. Sci.
PUBLISHED: 09-13-2011
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Cytochrome P450 (Cyp) enzymes from the first four families (Cyp1-4) play a major role in metabolizing xenobiotics, affecting drug pharmacokinetics and chemical-induced toxicity. Due to cloning of the mouse genome, many novel Cyp isoforms have been identified, but their tissue distribution of expression is unknown. This study compared the tissue distribution of all 78 Cyps from the Cyp1-4 families in C57BL/6 mice providing not only an indication of which tissues novel Cyps may have their greatest importance but also a cohesive comparison of the tissue distribution of all Cyp1-4 isoforms. Transcripts of the 78 Cyps were quantified by multiplex suspension arrays and quantitative real-time PCR in 14 tissues. Hierarchical clustering indicated that in male mice, 52% of the Cyp species were expressed highest in liver, 10% in kidney, 10% in duodenum/jejunum, 10% in testes, 5% in lung, and < 4% in colon, brain, heart, and stomach. Female mice had a similar pattern of Cyp messenger RNA expression; however, compared with males, females had 7% more Cyps that were liver predominant, 2% more Cyps that were stomach predominant, but 1% less Cyps that were kidney and lung predominant. Differences in gender expression were observed in 29 of the Cyps, with 24 being higher in females than males. Additionally, the data suggest a correlation between the spatial arrangement of genes within a gene cluster and their organ-predominant expression, indicating a common regulatory mechanism may be present within these clusters. In conclusion, this study provides novel data on the tissue distribution and gender-divergent expression of 78 functional mouse Cyp isoforms.
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Loss of organic anion transporting polypeptide 1a1 increases deoxycholic acid absorption in mice by increasing intestinal permeability.
Toxicol. Sci.
PUBLISHED: 09-13-2011
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Deoxycholic acid (DCA) is a known hepatotoxicant, a tissue tumor promoter, and has been implicated in colorectal cancer. Male mice are more susceptible to DCA toxicity than female mice. Organic anion transporting polypeptide 1a1 (Oatp1a1), which is known to transport bile acids (BAs) in vitro, is predominantly expressed in livers of male mice. In addition, the concentrations of DCA and its taurine conjugate (TDCA) are increased in serum of Oatp1a1-null mice. To investigate whether Oatp1a1 contributes to the gender difference in DCA toxicity in mice, wild-type (WT) and Oatp1a1-null mice were fed a 0.3% DCA diet for 7 days. After feeding DCA, Oatp1a1-null mice had 30-fold higher concentrations of DCA in both serum and livers than WT mice. Feeding DCA caused more hepatotoxcity in Oatp1a1-null mice than WT mice. After feeding DCA, Oatp1a1-null mice expressed higher BA efflux-transporters (bile salt-export pump, organic solute transporter (Ost)?/?, and multidrug resistance-associated protein [Mrp]2) and lower BA-synthetic enzymes (cytochrome P450 [Cyp]7a1, 8b1, 27a1, and 7b1) in livers than WT mice. Intravenous administration of DCA and TDCA showed that lack of Oatp1a1 does not decrease the plasma elimination of DCA or TDCA. After feeding DCA, the concentrations of DCA in ileum and colon tissues are higher in Oatp1a1-null than in WT mice. In addition, Oatp1a1-null mice have enhanced intestinal permeability. Taken together, the current data suggest that Oatp1a1 does not mediate the hepatic uptake of DCA or TDCA, but lack of Oatp1a1 increases intestinal permeability and thus enhances the absorption of DCA in mice.
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CYP2D plays a major role in berberine metabolism in liver of mice and humans.
Xenobiotica
PUBLISHED: 07-25-2011
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Berberine is a widely used plant extract for gastrointestinal infections, and is reported to have potential benefits in treatment for diabetes and hypercholesterolemia. It has been suggested that interactions between berberine-containing products and cytochromes P450 (CYPs) exist, but little is known about which CYPs mediate the metabolism of berberine in vivo. In this study, berberine metabolites in urine and feces of mice were analyzed, and the role that CYPs play in producing these metabolites were characterized in liver microsomes from mice (MLM) and humans (HLM), as well as recombinant human CYPs. Eleven berberine metabolites were identified in mice, including 5 unconjugated metabolites, mainly in feces, and 6 glucuronide and sulfate conjugates, predominantly in urine. Three novel berberine metabolites were observed. Three unconjugated metabolites of berberine were produced by MLM, HLM, and recombinant human CYPs. CYP2D6 was the primary recombinant human CYP producing these metabolites, followed by CYP1A2, 3A4, 2E1 and CYP2C19. The metabolism of berberine in MLM and HLM was decreased the most by a CYP2D inhibitor, and moderately by inhibitors of CYP1A and 3A. CYP2D plays a major role in berberine biotransformation, therefore, CYP2D6 pharmacogenetics and potential drug-drug interactions should be considered when berberine is used.
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Final report of the Cosmetic Ingredient Review Expert Panel safety assessment of polymethyl methacrylate (PMMA), methyl methacrylate crosspolymer, and methyl methacrylate/glycol dimethacrylate crosspolymer.
Int. J. Toxicol.
PUBLISHED: 07-21-2011
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Polymethyl methacrylate (PMMA) and related cosmetic ingredients methyl methacrylate crosspolymer and methyl methacrylate/glycol dimethacrylate crosspolymer are polymers that function as film formers and viscosity-increasing agents in cosmetics. The Food and Drug Administration (FDA) determination of safety of PMMA use in several medical devices, which included human and animal safety data, was used as the basis of safety of PMMA and related polymers in cosmetics by the Cosmetic Ingredient Review (CIR) Expert Panel.  The PMMA used in cosmetics is substantially the same as in medical devices.  The Panel concluded that these ingredients are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.
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Amended safety assessment of Sesamum indicum (sesame) seed oil, hydrogenated sesame seed oil, Sesamum indicum (sesame) oil unsaponifiables, and sodium sesameseedate.
Int. J. Toxicol.
PUBLISHED: 07-21-2011
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Sesamum indicum (sesame) seed oil and related cosmetic ingredients are derived from Sesamum indicum. Sesamum indicum (sesame) seed oil, sesamum indicum (sesame) oil unsaponifiables, and hydrogenated sesame seed oil function as conditioning agents. Sodium sesameseedate functions as a cleansing agent, emulsifying agent, and a nonaqueous viscosity increasing agent. These ingredients are neither skin irritants, sensitizers, teratogens, nor carcinogens at exposures that would result from cosmetic use. Both animal and human data relevant to the cosmetic use of these ingredients were reviewed. The CIR Expert Panel concluded that these ingredients are safe in the present practices of use and concentration as described in this safety assessment.
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Final report of the safety assessment of cosmetic ingredients derived from Zea mays (corn).
Int. J. Toxicol.
PUBLISHED: 07-21-2011
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Many cosmetic ingredients are derived from Zea mays (corn). While safety test data were not available for most ingredients, similarities in preparation and the resulting similar composition allowed extrapolation of safety data to all listed ingredients. Animal studies included acute toxicity, ocular and dermal irritation studies, and dermal sensitization studies. Clinical studies included dermal irritation and sensitization. Case reports were available for the starch as used as a donning agent in medical gloves. Studies of many other endpoints, including reproductive and developmental toxicity, use corn oil as a vehicle control with no reported adverse effects at levels used in cosmetics. While industry should continue limiting ingredient impurities such as pesticide residues before blending into a cosmetic formulation, the CIR Expert Panel determined that corn-derived ingredients are safe for use in cosmetics in the practices of use and concentration described in the assessment.
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Final report on the safety assessment of Cocos nucifera (coconut) oil and related ingredients.
Int. J. Toxicol.
PUBLISHED: 07-21-2011
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Cocos nucifera (coconut) oil, oil from the dried coconut fruit, is composed of 90% saturated triglycerides. It may function as a fragrance ingredient, hair conditioning agent, or skin-conditioning agent and is reported in 626 cosmetics at concentrations from 0.0001% to 70%. The related ingredients covered in this assessment are fatty acids, and their hydrogenated forms, corresponding fatty alcohols, simple esters, and inorganic and sulfated salts of coconut oil. The salts and esters are expected to have similar toxicological profiles as the oil, its hydrogenated forms, and its constituent fatty acids. Coconut oil and related ingredients are safe as cosmetic ingredients in the practices of use and concentration described in this safety assessment.
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Beneficial role of Nrf2 in regulating NADPH generation and consumption.
Toxicol. Sci.
PUBLISHED: 07-20-2011
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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that promotes the transcription of cytoprotective genes in response to oxidative and electrophilic stresses. Most functions of Nrf2 were identified by studying biological models with Nrf2 deficiency, however, little is known about the effects of graded Nrf2 activation. In the present study, genomic gene expression profiles by microarray analysis were characterized with a "gene dose-response" model in livers of Nrf2-null mice, wild-type mice, Kelch-like ECH associating protein 1 (Keap1)-knockdown (Keap1-KD) mice with enhanced Nrf2 activation, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum hepatic Nrf2 activation. Hepatic nuclear Nrf2 protein, glutathione concentrations, and known Nrf2 target genes were increased in a dose-dependent manner. In total, 115 genes were identified to be constitutively induced and 80 genes suppressed with graded Nrf2 activation. Messenger RNA of genes encoding enzymes in the pentose phosphate pathway and enzyme were low with Nrf2 deficiency and high with Nrf2 activation, indicating that Nrf2 is important for NADPH production. NADPH is the major reducing resource to scavenge oxidative stress, including regenerating glutathione and thioredoxin and is also used for anabolic pathways including lipid synthesis. High performance liquid chromatography-ultraviolet absorbance analysis confirmed that hepatic NADPH concentration was lowest in Nrf2-null mice and highest in Keap1-HKO mice. In addition, genes involved in fatty acid synthesis and desaturation were downregulated with graded Nrf2 activation. In conclusion, the present study suggests that Nrf2 protects against environmental insults by promoting the generation of NADPH, which is preferentially consumed by aiding scavenging of oxidative stress rather than fatty acid synthesis and desaturation.
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Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia.
Cell Metab.
PUBLISHED: 07-18-2011
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The association of type 2 diabetes with elevated plasma triglyceride (TG) and very low-density lipoproteins (VLDL), and intrahepatic lipid accumulation represents a pathophysiological enigma and an unmet therapeutic challenge. Here, we uncover a link between insulin action through FoxO1, bile acid (BA) composition, and altered lipid homeostasis that brings new insight to this longstanding conundrum. FoxO1 ablation brings about two signature lipid abnormalities of diabetes and the metabolic syndrome, elevated liver and plasma TG. These changes are associated with deficiency of 12?-hydroxylated BAs and their synthetic enzyme, Cyp8b1, that hinders the TG-lowering effects of the BA receptor, Fxr. Accordingly, pharmacological activation of Fxr with GW4064 overcomes the BA imbalance, restoring hepatic and plasma TG levels of FoxO1-deficient mice to normal levels. We propose that generation of 12?-hydroxylated products of BA metabolism represents a signaling mechanism linking hepatic lipid abnormalities with type 2 diabetes, and a treatment target for this condition.
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Dose-response of five bile acids on serum and liver bile Acid concentrations and hepatotoxicty in mice.
Toxicol. Sci.
PUBLISHED: 07-11-2011
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Feeding bile acids (BAs) to rodents has been used to study BA signaling and toxicity in vivo. However, little is known about the effect of feeding BAs on the concentrations of BAs in serum and liver as well as the dose of the fed BAs that causes liver toxicity. The present study was designed to investigate the relative hepatotoxicity of individual BAs by feeding mice cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), or ursodeoxycholic acid (UDCA) at concentrations of 0.01, 0.03, 0.1, 0.3, 1.0, or 3% in their diet for 7 days. The data demonstrate that (1) the ability of the fed BAs to produce hepatotoxicity is UDCA
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Repeated administration of berberine inhibits cytochromes P450 in humans.
Eur. J. Clin. Pharmacol.
PUBLISHED: 06-02-2011
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Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interactions between berberine-containing products and cytochromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses.
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Dose-response of berberine on hepatic cytochromes P450 mRNA expression and activities in mice.
J Ethnopharmacol
PUBLISHED: 05-23-2011
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Berberine is an isoquinoline alkaloid isolated from the root and bark of plants such as goldenseal, Berberis, and Chinese goldthread. Berberine-containing crude drugs have been used as an antimicrobial remedy against gastrointestinal infections for thousands of years. It is also widely used in Asian countries for diabetes, hypertension, and hypercholesterolemia therapy.
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Organic anion transporting polypeptides in the hepatic uptake of PBDE congeners in mice.
Toxicol. Appl. Pharmacol.
PUBLISHED: 05-17-2011
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BDE47, BDE99 and BDE153 are the predominant polybrominated diphenyl ether (PBDE) congeners detected in humans and can induce drug metabolizing enzymes in the liver. We have previously demonstrated that several human liver organic anion transporting polypeptides (humans: OATPs; rodents: Oatps) can transport PBDE congeners. Mice are commonly used to study the toxicity of chemicals like the PBDE congeners. However, the mechanism of the hepatic PBDE uptake in mice is not known. Therefore, the purpose of the current study was to test the hypothesis that BDE47, BDE99, and BDE153 are substrates of mouse hepatic Oatps (Oatp1a1, Oatp1a4, Oatp1b2, and Oatp2b1). We used Human Embryonic Kidney 293 (HEK293) cells transiently expressing individual Oatps and quantified the uptake of BDE47, BDE99, and BDE153. Oatp1a4, Oatp1b2, and Oatp2b1 transported all three PBDE congeners, whereas Oatp1a1 did transport none. Kinetic studies demonstrated that Oatp1a4 and Oatp1b2 transported BDE47 with the greatest affinity, followed by BDE99 and BDE153. In contrast, Oatp2b1 transported all three PBDE congeners with similar affinities. The importance of hepatic Oatps for the liver accumulation of BDE47 was confirmed using Oatp1a4-, and Oatp1b2-null mice.
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Characterization of organic anion-transporting polypeptide (Oatp) 1a1 and 1a4 null mice reveals altered transport function and urinary metabolomic profiles.
Toxicol. Sci.
PUBLISHED: 05-10-2011
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Organic anion-transporting polypeptides (Oatp) 1a1 and 1a4 were deleted by homologous recombination, and mice were characterized for Oatp expression in liver and kidney, transport in isolated hepatocytes, in vivo disposition of substrates, and urinary metabolomic profiles. Oatp1a1 and Oatp1a4 proteins were undetected in liver, and both lines were viable and fertile. Hepatic constitutive messenger RNAs (mRNAs) for Oatp1a4, 1b2, or 2b1 were unchanged in Oatp1a1?/? mice, whereas renal Oatp1a4 mRNA decreased approximately 50% (both sexes). In Oatp1a4?/? mice, no changes in constitutive mRNAs for other Oatps were observed. Uptake of estradiol-17?-D-glucuronide and estrone-3-sulfate in primary hepatocytes decreased 95 and 75%, respectively, in Oatp1a1?/? mice and by 60 and 30%, respectively, in Oatp1a4?/? mice. Taurocholate uptake decreased by 20 and 50% in Oatp1a1?/? and Oatp1a4?/? mice, respectively, whereas digoxin was unaffected. Plasma area under the curve (AUC) for estradiol-17?-D-glucuronide increased 35 and 55% in male and female Oatp1a1?/? mice, respectively, with a concurrent 50% reduction in liver-to-plasma ratios. In contrast, plasma AUC or tissue concentrations of estradiol-17?-D-glucuronide were unchanged in Oatp1a4?/? mice. Plasma AUCs for dibromosulfophthalein increased nearly threefold in male Oatp1a1?/? and Oatp1a4?/? mice, increased by 40% in female Oatp1a4?/? mice, and were unchanged in female Oatp1a1?/? mice. In both lines, no changes in serum ALT, bilirubin, and cholesterol were noted. NMR analyses showed no generalized increase in urinary excretion of organic anions. However, urinary excretion of taurine decreased by 30-40% and was accompanied by increased excretion of isethionic acid, a taurine metabolite generated by intestinal bacteria, suggesting some perturbations in intestinal bacteria distribution.
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Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis.
Toxicol. Appl. Pharmacol.
PUBLISHED: 04-25-2011
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Previous studies demonstrate that Nrf2, a master regulator of antioxidative responses, is essential in mediating induction of many antioxidative enzymes by acute activation of the AhR. However, the role of Nrf2 in protecting against oxidative stress and DNA damage induced by sustained activation of the AhR remains unknown and was investigated herein. Tissue and blood samples were collected from wild-type (WT) and Nrf2-null mice 21 days after administration of a low-toxic dose (10 ?g/kg ip) of TCDD. Only Nrf2-null mice lost body weight after TCDD treatment; however, blood levels of ALT were not markedly changed in either genotype, indicating a lack of extensive necrosis. Compared to livers of TCDD-treated WT mice, livers of TCDD-treated Nrf2-null mice had: 1) degenerated hepatocytes, lobular inflammation, marked fat accumulation, and higher mRNA expression of inflammatory and fibrotic genes; 2) depletion of glutathione, elevation in lipid peroxidation and marker of DNA damage; 3) attenuated induction of phase-II enzymes Nqo1, Gsta1/2, and Ugt2b35 mRNAs, but higher induction of cytoprotective Ho-1, Prdx1, Trxr1, Gclc, and Epxh1 mRNAs; 4) higher mRNA expression of Fgf21 and triglyceride-synthesis genes, but down-regulation of bile-acid-synthesis genes and cholesterol-efflux transporters; and 5) trend of induction/activation of c-jun and NF-kB. Additionally, TCDD-treated Nrf2-null mice had impaired adipogenesis in white adipose tissue. In conclusion, Nrf2 protects livers of mice against oxidative stress, DNA damage, and steatohepatitis induced by TCDD-mediated sustained activation of the AhR. The aggravated hepatosteatosis in TCDD-treated Nrf2-null mice is due to increased lipogenesis in liver and impaired lipogenesis in white adipose tissue.
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