Eichelbaum M, Kroemer H K, Mikus G
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Toxicol Lett. 1992 Dec;64-65 Spec No:115-22. doi: 10.1016/0378-4274(92)90180-r.
Drug metabolizing enzymes are of paramount importance in drug detoxification as well as chemical mutagenesis, carcinogenesis and toxicity via metabolic activation. Thus genetically determined differences in the activity of these enzymes can influence individual susceptibility to adverse drug reactions, drug induced diseases and certain types of chemically induced cancers. The genetic polymorphisms of three human drug metabolizing enzymes, namely N-acetyltransferase and two cytochrome P-450 isozymes (P-4502D6: debrisoquine/sparteine polymorphism, P-4502C8-10: mephenytoin polymorphism) have been firmly established. Based on the metabolic handling of certain probe drugs, the population can be divided into two phenotypes: the rapid acetylator/extensive metabolizer and slow acetylator/poor metabolizer. These polymorphisms have provided useful tools to study the relationship between genetically determined differences in the activity of drug metabolizing enzymes and the risk for adverse drug reactions and certain types of chemically-induced diseases and cancers. With regard to the susceptibility of the two phenotypes, drug mediated toxicity for the following scenarios can be anticipated. (1) The toxicity of the drug is caused by the parent compound and the elimination of the drug proceeds exclusively via the polymorphic enzyme. No alternate pathways of biotransformation are available. Thus the slow acetylator/poor metabolizer phenotype will be more prone to such a type of toxicity since, at the same level of exposure, this phenotype will accumulate the drug as a result of impaired metabolism (e.g. isoniazid polyneuropathy, perhexiline polyneuropathy, pesticide induced Parkinsons disease). (2) The polymorphic pathway is a major route of detoxification. Impairment of this pathway shifts the metabolism to an alternate pathway via which a reactive intermediate is being formed. In such a situation the slow acetylator/poor metabolizer phenotype constitutes a major risk factor for toxicity (e.g. isoniazid hepatotoxicity). (3) The toxicity is mediated by a reactive intermediate generated by a polymorphic enzyme. Hence extensive metabolizers are at a much higher risk than poor metabolizers to develop toxicity or cancer (e.g. bronchial carcinoma in smokers, not chemically induced aggressive bladder cancer).
药物代谢酶在药物解毒以及通过代谢活化产生化学诱变、致癌作用和毒性方面至关重要。因此，这些酶活性的基因决定差异会影响个体对药物不良反应、药物诱导疾病和某些类型化学诱导癌症的易感性。三种人类药物代谢酶的基因多态性，即N - 乙酰转移酶和两种细胞色素P - 450同工酶（P - 4502D6：异喹胍/司巴丁多态性，P - 4502C8 - 10：美芬妥英多态性）已得到确凿证实。根据某些探针药物的代谢情况，人群可分为两种表型：快速乙酰化者/广泛代谢者和缓慢乙酰化者/代谢不良者。这些多态性为研究药物代谢酶活性的基因决定差异与药物不良反应以及某些类型化学诱导疾病和癌症风险之间的关系提供了有用工具。关于这两种表型的易感性，可以预期以下几种情况下药物介导的毒性。（1）药物毒性由母体化合物引起，药物消除仅通过多态性酶进行。不存在生物转化的替代途径。因此，缓慢乙酰化者/代谢不良者表型更容易出现此类毒性，因为在相同暴露水平下，该表型由于代谢受损会积累药物（例如异烟肼多发性神经病、苄丙咯多发性神经病、农药诱导的帕金森病）。（2）多态性途径是主要的解毒途径。该途径受损会使代谢转向通过其形成反应性中间体的替代途径。在这种情况下，缓慢乙酰化者/代谢不良者表型是毒性的主要危险因素（例如异烟肼肝毒性）。（3）毒性由多态性酶产生的反应性中间体介导。因此，广泛代谢者比代谢不良者发生毒性或癌症的风险要高得多（例如吸烟者的支气管癌，而非化学诱导的侵袭性膀胱癌）。
