Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J
Department of Pharmacology, Clinical Pharmacology, University of Cologne, Köln, Germany.
Pharmacogenomics J. 2008 Feb;8(1):4-15. doi: 10.1038/sj.tpj.6500462. Epub 2007 Jun 5.
For most drug-metabolizing enzymes (DMEs), the functional consequences of genetic polymorphisms have been examined. Variants leading to reduced or increased enzymatic activity as compared to the wild-type alleles have been identified. This review tries to define potential fields in the therapy of major medical conditions where genotyping (or phenotyping) of genetically polymorphic DMEs might be beneficial for drug safety or therapeutic outcome. The possible application of genotyping is discussed for depression, cardiovascular diseases and thromboembolic disorders, gastric ulcer, malignant diseases and tuberculosis. Some drugs used for relief of these ailments are metabolized with participation of genetically polymorphic DMEs including CYP2D6, CYP2C9, CYP2C19, thiopurine-S-methyltransferase, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase and N-acetyltransferase type 2. Current evidence suggests that taking genetically determined metabolic capacities of DMEs into account has the potential to improve individual risk/benefit relationship. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on DME variants can be established.
对于大多数药物代谢酶（DMEs），已对基因多态性的功能后果进行了研究。与野生型等位基因相比，导致酶活性降低或增加的变体已被鉴定出来。本综述试图确定在主要医疗状况的治疗中，基因多态性DMEs的基因分型（或表型分型）可能对药物安全性或治疗结果有益的潜在领域。讨论了基因分型在抑郁症、心血管疾病和血栓栓塞性疾病、胃溃疡、恶性疾病和结核病中的可能应用。用于缓解这些疾病的一些药物在基因多态性DMEs（包括CYP2D6、CYP2C9、CYP2C19、硫嘌呤 - S - 甲基转移酶、二氢嘧啶脱氢酶、尿苷二磷酸葡萄糖醛酸转移酶和N - 乙酰转移酶2型）的参与下进行代谢。目前的证据表明，考虑DMEs的基因决定的代谢能力有可能改善个体的风险/效益关系。然而，在基于DME变体的“个性化医学”范式得以确立之前，还需要更多具有临床终点的前瞻性研究。
