17.11
生物活化与组织毒性
生物活化是一种代谢过程，可将反应性较低的物质转化为高反应性代谢物，从而引发组织毒性。这种转化可导致多种毒性效应，包括致癌作用和致畸作用。反应性代谢物分为两类：亲电体和自由基。
亲电体是电子缺乏的化学物种，主要由细胞色素 P450 在含碳、氮或硫的化合物代谢过程中产生。重要的亲电性代谢物包括环氧化物、…
生物活化是一种由酶介导的过程，可将惰性物质转化为高活性代谢产物，例如亲电子物质和自由基。这些生物活性代谢产物与组织相互作用，引发多种不良反应，包括肝毒性和肾毒性。
亲电试剂（如环氧化物、羟胺和亚硝基衍生物）是缺电子对的物质。它们通常在异源物质代谢过程中，由细胞色素P450介导的代谢反应生成，作为活性中间体出现。
通常，这些亲电物会通过与谷胱甘肽结合而失活。然而，当其过量时，可共价结合于DNA等亲核大分子，导致突变和癌症。
自由基具有未成对电子，可为阳离子、阴离子或中性物质。在代谢反应中，NADPH-细胞色素P450系统或还原酶通常会生成自由基。
羟基自由基和超氧阴离子等无机自由基可引起广泛的组织损伤，导致突变或癌症。
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Q1: What is bioactivation and how does it lead to tissue toxicity?
Bioactivation is an enzyme-mediated process that converts inert substances into highly reactive metabolites, such as electrophiles and free radicals. These bioactive metabolites interact with tissues, causing various adverse effects including hepatotoxicity and nephrotoxicity. The transformation initiates tissue toxicity and can lead to carcinogenesis and teratogenesis.
Q2: How are electrophiles generated during drug metabolism?
Electrophiles are electron-deficient species produced primarily by cytochrome P450 during metabolism of compounds containing carbon, nitrogen, or sulfur. Significant electrophilic metabolites include epoxides, hydroxylamines, and nitroso derivatives. These reactive intermediates are typically generated as part of xenobiotic processing and can bind covalently to nucleophilic macromolecules like DNA.
Q3: What happens when electrophiles exceed the body's detoxification capacity?
When electrophiles are in excess, they can bind covalently to nucleophilic macromolecules like DNA, leading to mutations and cancer. Typically, these electrophiles are inactivated by glutathione conjugation, but when this defense mechanism is overwhelmed, toxic effects accumulate and cellular damage occurs.
Q4: What are free radicals and how do they cause tissue damage?
Free radicals are highly reactive molecules with unpaired electrons that exist as cations, anions, or neutral species. They are generated by the NADPH-cytochrome P450 system or reductases during metabolic reactions. Inorganic free radicals like hydroxyl radical and superoxide anion cause extensive tissue damage through peroxidation of cellular components, potentially leading to mutation or cancer.
Q5: How does the body defend against electrophile-induced toxicity?
The primary defense against electrophiles is their inactivation by sulfur-containing nucleophiles like glutathione through conjugation reactions. This mechanism neutralizes reactive electrophiles before they can bind to DNA and other cellular components. When glutathione levels are adequate, most electrophiles are safely eliminated from the body.
Q6: What antioxidant systems protect cells from free radical damage?
The body's defense against free radical-induced toxicity includes using glutathione, membrane structure control, and antioxidant scavengers such as vitamins A, E, and C. Additionally, specialized enzymes inactivate oxygen-derived free radicals. This intricate defense system underscores the body's capacity to manage adverse effects of bioactivation and related drug toxicity dose dependent reactions.
Q7: What are the main types of reactive metabolites produced during bioactivation?
Reactive metabolites are classified into two main types: electrophiles and free radicals. Electrophiles are electron-deficient species including epoxides, hydroxylamines, and nitroso derivatives. Free radicals are molecules with unpaired electrons, including organic and inorganic types like hydrogen peroxide and superoxide anion, both capable of causing significant cellular damage.