Park B K, Pirmohamed M, Kitteringham N R
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
Pharmacol Ther. 1995;68(3):385-424. doi: 10.1016/0163-7258(95)02013-6.
The human cytochrome P450 enzyme system metabolises a wide array of xenobiotics to pharmacologically inactive metabolites, and occasionally, to toxicologically active metabolites. Impairment of cytochrome P450 activity, which may be either genetic or environmental, may lead to toxicity caused by the parent compound itself. In practise, this usually only applies to drugs that have a narrow therapeutic index and when their clearance is critically dependent upon the fraction normally metabolised by that pathway. P450 enzymes may also convert the drug to a chemically reactive metabolite, which, if not detoxified, may lead to various forms of hepatic and extrahepatic toxicity, including cellular necrosis, hypersensitivity, teratogenicity, and carcinogenicity, depending on the site of formation and the relative stability of the metabolite, and the cellular macromolecule with which it reacts. Variation in the regulation and expression of the drug metabolising enzymes may play a key role in both interindividual variation in sensitivity to drug toxicity and tissue-specific damage. Avoidance of toxicity may be possible in rare instances by prediction of individual susceptibility or by designing new chemical entities that are metabolised by a range of enzymes (both cytochromes P450 and others) and do not undergo bioactivation.
人类细胞色素P450酶系统可将多种外源性物质代谢为药理活性失活的代谢产物，偶尔也会代谢为毒理活性代谢产物。细胞色素P450活性的损害，可能是遗传因素或环境因素导致的，可能会引发母体化合物本身所致的毒性。在实际应用中，这通常仅适用于治疗指数较窄的药物，以及其清除率严重依赖于该途径正常代谢部分的药物。P450酶还可能将药物转化为化学反应性代谢产物，如果该代谢产物未被解毒，可能会导致各种形式的肝毒性和肝外毒性，包括细胞坏死、超敏反应、致畸性和致癌性，这取决于代谢产物的形成部位、相对稳定性以及与之反应的细胞大分子。药物代谢酶的调节和表达差异可能在个体对药物毒性敏感性的个体间差异以及组织特异性损伤中起关键作用。在极少数情况下，通过预测个体易感性或设计可被多种酶（细胞色素P450酶及其他酶）代谢且不会发生生物活化的新化学实体，有可能避免毒性。
