Combined Effects of Cadmium and Nickel on Testicular Xenobiotic Metabolizing Enzymes in Rats

Biological Trace Element Research. Nov, 2002  |  Pubmed ID: 12449241

When male rats were given a single dose of cadmium (Cd) (3.58 mg CdCl2 x H2O/kg, i.p.) 72 hr prior to sacrifice, the testicular 7-ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (EPNP), and cumene hydroperoxide (CHPx) decreased significantly as compared to controls. Cd also inhibited reduced glutathione (GSH) level while increasing the lipid peroxidation (LP) level significantly. When the animals were given a single dose of nickel (Ni) (59.5 mg NiCl2 x 6H2O/kg, i.p.) 16 hr prior to sacrifice, significant decreases were observed in EROD and GST activities toward CDNB, EAA, EPNP, and CHPx, and GSH level. No significant alterations were noted in DCNB GST activity and LP level by Ni. For the combined treatment, rats received the single dose of Ni 56 hr after the single dose of Cd and were killed 16 hr later. In these animals, lesser depressions were observed on EROD activity and LP level than those of Cd alone. The combination of metals significantly inhibited GST activities and GSH level but not to a greater degree than noted by Cd or Ni alone. Plasma testosterone levels of Cd-, Ni-, and combination-treated rats decreased significantly compared to controls. The strongest depression was achieved by Cd alone. Cd, both alone and in combination with Ni, increased the tissue Ni uptake significantly. Ni, however, did not produce such an effect on the tissue uptake of Cd in either case. Cd treatment caused interstitial edema and coagulation necrosis in seminiferous tubules and also caused fibrinoidal necrosis in vascular endothelium. Ni treatment did not produce any pathological testicular alterations compared to controls. Combined treatment produced fewer pathological alterations (i.e., only interstitial edema) than that of Cd treatment. These results reveal that the combination of Cd and Ni does nothave a synergistic effect on testicular xenobiotic metabolizing enzymes, and in contrast, Ni has an ameliorating effect on pathological disturbances caused by Cd alone in the rat testis.

Polymorphisms of Cytochrome P450 1A1, Glutathione S-transferases M1 and T1 in a Turkish Population

Toxicology Letters. Jun, 2004  |  Pubmed ID: 15177667

Intra-ethnic as well as inter-ethnic differences are known to exist in the frequencies of cytochrome P450 (CYP) 1A1, glutathione S-transferase (GST) M1, and GSTT1 gene polymorphisms with which associations have been shown for several cancers. In this study, CYP1A1 m2, GSTM1, and GSTT1 gene polymorphisms were determined among 133 healthy individuals of a Turkish population. On the basis of polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) methodology, the frequency of CYP1A1 m2 mutation was determined. The multiplex PCR protocol was used to determine the frequency of the deleted genotypes of both GSTM1 and GSTT1 genes. The frequencies of Ile/Ile (wild type), Ile/Val (heterozygous variant), and Val/Val (homozygous variant) CYP1A1 m2 genotypes were 90.2%, 9.8%, and 0%, respectively. The frequencies of the deleted GSTM1 (null) and GSTT1 (null) genotypes were 51.9% and 17.3%, respectively. These results show that the frequencies of the CYP1A1 m2, GSTM1, and GSTT1 gene polymorphisms in a Turkish population are similar to Caucasian populations.

Regulation of Lipolytic Activity by Long-chain Acyl-coenzyme A in Islets and Adipocytes

American Journal of Physiology. Endocrinology and Metabolism. Dec, 2005  |  Pubmed ID: 16091387

Intracellular lipolysis is a major pathway of lipid metabolism that has roles, not only in the provision of free fatty acids as energy substrate, but also in intracellular signal transduction. The latter is likely to be particularly important in the regulation of insulin secretion from islet beta-cells. The mechanisms by which lipolysis is regulated in different tissues is, therefore, of considerable interest. Here, the effects of long-chain acyl-CoA esters (LC-CoA) on lipase activity in islets and adipocytes were compared. Palmitoyl-CoA (Pal-CoA, 1-10 microM) stimulated lipase activity in islets from both normal and hormone-sensitive lipase (HSL)-null mice and in phosphatase-treated islets, indicating that the stimulatory effect was neither on HSL nor phosphorylation dependent. In contrast, we reproduced the previously published observations showing inhibition of HSL activity by LC-CoA in adipocytes. The inhibitory effect of LC-CoA on adipocyte HSL was dependent on phosphorylation and enhanced by acyl-CoA-binding protein (ACBP). In contrast, the stimulatory effect on islet lipase activity was blocked by ACBP, presumably due to binding and sequestration of LC-CoA. These data suggest the following intertissue relationship between islets and adipocytes with respect to fatty acid metabolism, LC-CoA signaling, and lipolysis. Elevated LC-CoA in islets stimulates lipolysis to generate a signal to increase insulin secretion, whereas elevated LC-CoA in adipocytes inhibits lipolysis. Together, these opposite actions of LC-CoA lower circulating fat by inhibiting its release from adipocytes and promoting fat storage via insulin action.

Biological Monitoring of Environmental Exposure to Polycyclic Aromatic Hydrocarbons: 1-hydroxypyrene in Urine of Turkish Coke Oven Workers

Bulletin of Environmental Contamination and Toxicology. Apr, 2006  |  Pubmed ID: 16688535

Synthesis and Antioxidant Properties of Novel N-H and N-substituted Propanamide Derivatives

Archiv Der Pharmazie. Mar, 2007  |  Pubmed ID: 17315261

The interest in the application of antioxidants for medical treatment has been growing recently. A lot of evidence has proven the link between the development of human diseases and oxidative stress. Indole derivatives were found to be very effective in protecting against oxidative stress. Recent exciting findings have demonstrated that several indole derivatives (IDs) are strong inhibitors of superoxide anion (SOD) and lipid peroxidation (LP). In this study, a series of novel N-H and N-substituted indole-3-propanamide derivatives (I3PADs) have been prepared and their efficiencies were investigated towards SOD and LP. Among the synthesized I3PADs, compounds 5 and 7-12 significantly inhibited O2*- in the range of 94-100%. In addition, N-H I3PADs showed a stronger inhibitory effect (compounds 1-5, 56-83%) on lipid peroxidation levels than SOD.

Polymorphisms of Microsomal Epoxide Hydrolase and Glutathione S-transferase P1 in a Male Turkish Population

International Journal of Toxicology. Jan-Feb, 2007  |  Pubmed ID: 17365145

Polymorphic genes encoding drug-metabolizing enzymes may account for interindividual differences in certain types of diseases especially cancer. In this study, microsomal epoxide hydrolase (EPHX1) and glutathione S-transferase P1 (GSTP1) gene polymorphisms were determined among 133 healthy males of a Turkish population. Frequencies of EPHX1 and GSTP1 gene polymorphisms were determined by using the polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) method. The observed genotype frequencies of EPHX1 exon 3 were Tyr113Tyr:50.4%, Tyr113His: 42.1%, His113His: 7.5% and EPHX1 exon 4 were His139His: 69.2%, His139Arg: 28.6%, Arg133Arg: 2.2%. GSTP1 exon 5 genotype frequencies were Ile105Ile: 58.7%, Ile105Val: 35.3%, Val105Val: 6.0% and GSTP1 exon 6 genotype frequencies were Ala114Ala: 85.0%, Ala114Val: 14.3%, Val114Val: 0.7%. These results reveal that the frequencies of EPHX1 and GSTP1gene polymorphisms in a small sampling of males within a Turkish population are similar to European Caucasian populations.

Synthesis and Evaluation of Novel N-H and N-substituted Indole-2- and 3-carboxamide Derivatives As Antioxidants Agents

Journal of Enzyme Inhibition and Medicinal Chemistry. Aug, 2007  |  Pubmed ID: 17847713

We have previously reported on the synthesis of novel indole derivatives where some compounds showed significant antioxidant activity. Here, we report the synthesis of novel N-H and N-substituted indole-2- and 3-carboxamide derivatives and investigated their antioxidant role in order to identify structural characteristics responsible for activity. Although all compounds showed a strong inhibitory (95-100%) effect on superoxide anion (SOD) only compounds 4, 5 and 6 showed simliar potency for the inhibition of lipid peroxidation (81-94%) which revealed that compounds 4, 5 and 6 possessed highly potent antioxidant properties. Substitution in the 1-position of the indole ring caused the significant differences between the activity results regarding lipid peroxidation inhibition.

Involvement of Estrogen-related Receptors in Transcriptional Response to Hypoxia and Growth of Solid Tumors

Proceedings of the National Academy of Sciences of the United States of America. Jun, 2008  |  Pubmed ID: 18509053

The development of intratumoral hypoxia is a universal hallmark of rapidly growing solid tumors. Adaptation to the hypoxic environment, which is critical for tumor cell survival and growth, is mediated primarily through a hypoxia-inducible factor (HIF)-dependent transcriptional program. HIF activates genes that facilitate crucial adaptive mechanisms including increased glucose uptake and glycolysis and tumor angiogenesis, making it an important therapeutic target. However, the HIF-dependent transcriptional mechanism remains incompletely understood, and targeting HIF is a difficult endeavor. Here, we show that the orphan nuclear receptor estrogen-related receptors (ERRs) physically interact with HIF and stimulate HIF-induced transcription. Importantly, ERRs appear to be essential for HIF's function. Transcriptional activation of hypoxic genes in cells cultured under hypoxia is largely blocked by suppression of ERRs through expression of a dominant negative form of ERR or treatment with a pharmacological ERR inhibitor, diethylstilbestrol. Systematic administration of diethylstilbestrol severely diminished growth and angiogenesis of tumor xenografts in vivo. Because nuclear receptors are outstanding targets for drug discovery, the findings not only may offer mechanistic insights into HIF-mediated transcription but also may open new avenues for targeting the HIF pathway for cancer therapy.

CYP and GST Polymorphisms and Survival in Advanced Non-small Cell Lung Cancer Patients

Neoplasma. 2010  |  Pubmed ID: 20845989

Several polymorphisms in cytochrome P-450s (CYP)s and Glutathione S-transferases (GST)s have been reported to be associated with survival rates of patients with non-small cell lung cancer (NSCLC) but the studies in this regard are scarce and the results are contradictory. In this study, CYP1A1 (Ile462Val), CYP1B1(Asn453Ser), GST M1, GSTP1 exon 5 (Ile105Val) and exon 6(Ala114Val) and GSTT1 polymorphisms were determined in 138 patients with advanced NSCLC to evaluate their role in survival. Of the studied CYP and GST polymorphisms only GSTP1 exon 6 variant significantly altered (improved) the survival compared to wild type (p=0.036) with median survival of 22.2 months and 16.1 months, respectively. Multivariate analysis also revealed a significant reduction of adjusted hazard ratio of death associated only with the GSTP1 exon 6 variant genotype of 0.45 (95% confidence interval (95% CI), 0.23-0.89, p=0.022). These results show that the GSTP1 exon 6 variant genotype is associated with improved survival in the patients with advanced NSCLC. Keywords: Cytochrome P-450, glutathione S-transferase, non small cell lung cancer, polymorphism, survival.

Regenerative Chemical Biology: Current Challenges and Future Potential

Chemistry & Biology. Apr, 2011  |  Pubmed ID: 21513877

The enthusiasm surrounding the clinical potential of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) is tempered by the fact that key issues regarding their safety, efficacy, and long-term benefits have thus far been suboptimal. Small molecules can potentially relieve these problems at major junctions of stem cell biology and regenerative therapy. In this review we will introduce recent advances in these important areas and the first generation of small molecules used in the regenerative context. Current chemical biology studies will provide the archetype for future interdisciplinary collaborations and improve clinical benefits of cell-based therapies.

Response of Estrogen Receptor-positive Breast Cancer Tumorspheres to Antiestrogen Treatments

PloS One. 2011  |  Pubmed ID: 21533195

Estrogen signaling plays a critical role in the pathogenesis of breast cancer. Because the majority of breast carcinomas express the estrogen receptor ERα, endocrine therapy that impedes estrogen-ER signaling reduces breast cancer mortality and has become a mainstay of breast cancer treatment. However, patients remain at continued risk of relapse for many years after endocrine treatment. It has been proposed that cancer recurrence may be attributed to cancer stem cells (CSCs)/tumor-initiating cells (TICs). Previous studies in breast cancer have shown that such cells can be enriched and propagated in vitro by culturing the cells in suspension as mammospheres/tumorspheres. Here we established tumorspheres from ERα-positive human breast cancer cell line MCF7 and investigated their response to antiestrogens Tamoxifen and Fulvestrant. The tumorsphere cells express lower levels of ERα and are more tumorigenic in xenograft assays than the parental cells. Both 4-hydroxytamoxifen (4-OHT) and Fulvestrant attenuate tumorsphere cell proliferation, but only 4-OHT at high concentrations interferes with sphere formation. However, treated tumorsphere cells retain the self-renewal capacity. Upon withdrawal of antiestrogens, the treated cells resume tumorsphere formation and their tumorigenic potential remains undamaged. Depletion of ERα shows that ERα is dispensable for tumorsphere formation and xenograft tumor growth in mice. Surprisingly, ERα-depleted tumorspheres display heightened sensitivity to 4-OHT and their sphere-forming capacity is diminished after the drug is removed. These results imply that 4-OHT may inhibit cellular targets besides ERα that are essential for tumorsphere growth, and provide a potential strategy to sensitize tumorspheres to endocrine treatment.

Association Between GSTM1, GSTT1, and GSTP1 Polymorphisms and Lung Cancer Risk in a Turkish Population

Molecular Biology Reports. Dec, 2011  |  Pubmed ID: 22207177

Several studies focused on investigating genetic polymorphisms in order to estimate genetic contribution to lung cancer often showed conflicting results. In this study, we investigated the role of GSTM1, GSTT1, GSTP1 exon 5 and exon 6 polymorphisms on developing lung cancer and histological subtypes in 213 lung cancer patients and 231 controls. GSTM1 null, GSTT1 null, and GSTP1 exon 5 variant genotypes did not show a significant risk for developing lung cancer overall. Significant association was noted between GSTP1 exon 6 variant genotypes and overall lung cancer risk (OR 2.17, 95% CI 1.25-3.78; P = 0.006). These results show that GSTP1 exon 6 polymorphism might be an important factor in determining lung cancer susceptibility in a Turkish population.