Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication
Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication
复制标题
DOI：
10.1046/j.1365-2362.33.s2.3.x
复制
发表时间：
2003-11-01
影响因子：
5.5
通讯作者：
Cascorbi, I
中科院分区：
文献类型：
--
作者：
Cascorbi, I
许多药物的药代动力学的个体间差异通常是由于药物代谢酶的遗传多态性。最重要的是细胞色素P4502 D 6（CYP 2D 6），也称为异喹/鹰爪豆碱羟化酶。它催化超过20%的药物在人体肝脏中代谢的羟基化或去甲基化，如神经安定药，抗抑郁药，一些β-受体阻滞剂和许多其他药物，如可待因。大约7%-10%的高加索人由于基因的缺失和移码或剪接位点突变而缺乏任何CYP 2D 6活性。大约1%-3%的中欧人，但高达29%的欧洲人显示基因重复，导致所谓的超快速代谢率升高。与此同时，现在对差、中、快和超快代谢者的遗传背景有了更好的了解，从而能够更精确地基于DNA基因分型预测血浆水平。由于有证据表明，药物消除恶化部分原因是药物副作用，CYP 2D 6基因分型可能有助于个性化，从而优化药物治疗。
Interindividual differences in the pharmacokinetics of a number of drugs are often due to hereditary polymorphisms of drug-metabolizing enzymes. Most important is cytochrome P4502D6 (CYP2D6), also known as debrisoquine/sparteine hydroxylase. It catalyzes hydroxylation or demethylation of more than 20% of drugs metabolized in the human liver, such as neuroleptics, antidepressants, some beta-blockers and many others like codeine. About 7%-10% of Caucasians lack any CYP2D6 activity due to deletions and frame-shift or splice-site mutations of the gene. About 1%-3% of Middle-Europeans, but up to 29% of Ethiopians display gene duplications, leading to elevated so-called ultrarapid metabolization rates. Meanwhile there is now a much better understanding of the genetic background of poor, intermediate, extensive and ultrarapid metabolizers, enabling a more precise DNA genotyping-based prediction of plasma levels. Since there is evidence that deteriorated drug elimination partly accounts for drug side-effects, CYP2D6 genotyping could contribute to an individualized and therefore optimized drug therapy.