Bernard Stephen, Neville Kathleen A, Nguyen Anne T, Flockhart David A
Division of Hematology and Medical Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7305, USA.
Oncologist. 2006 Feb;11(2):126-35. doi: 10.1634/theoncologist.11-2-126.
DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity. Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT(3)-receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country's wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug-drug interactions increases.
已在编码多种细胞色素P450（CYP）酶的基因中鉴定出DNA多态性，这导致药物清除率在个体间存在广泛差异。CYP2D6代谢大量临床使用的药物，CYP2D6同工酶的基因变异导致代谢活性水平不同，在某些情况下具有临床重要性。该基因多态性所引起的临床效应的确切性质取决于所讨论的药物以及所表达的特定变异等位基因，因为个体变异会导致具有一系列酶活性水平的不同表型。已有文献记载多种药物因CYP2D6变异而导致疗效受损，本综述考虑了多个实例，包括5-羟色胺（5-HT）3受体拮抗剂，这些药物用于肿瘤支持治疗中预防恶心和呕吐。除了格拉司琼外，CYP2D6参与所有最常用药物的代谢，因此它们的疗效和副作用可能会受到CYP2D6多态性的影响。许多国家的研究表明，CYP2D6等位基因频率存在显著的种族差异。然而，由于美国种族多样性广泛，其人群中多态性的发生率难以确定。随着强大的临床检测方法广泛应用，以及多种药物的使用和随之而来的药物相互作用风险增加，CYP2D6多态性可能会变得更加重要。
