Bertilsson L
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
Clin Pharmacokinet. 1995 Sep;29(3):192-209. doi: 10.2165/00003088-199529030-00005.
The isoenzymes which catalyse the polymorphic hydroxylations of debrisoquine/sparteine and S-mephenytoin are cytochromes P450 2D6 and P450 2C19 (CYP2D6 and CYP2C19), respectively. CYP2D6 is involved in the stereospecific metabolism of several important groups of drugs, for example antiarrhythmics, antidepressants and neuroleptics. About 7% of Caucasians but only 1% of Orientals are poor metabolisers (PMs) of debrisoquine. The most common mutated allele CYP2D6B in Caucasian PMs is almost absent from their Oriental counterparts. On the other hand, the mean activity of CYP2D6 in Oriental extensive metabolisers (EMs) is lower than that in Caucasian EMs. This is due to the frequent distribution of a partially deficient CYP2D6 allele causing a Pro34-->Ser amino acid exchange in as many as 50% of Oriental alleles. This is the molecular genetic basis for slower metabolism of antidepressants and neuroleptics observed in Oriental compared with Caucasian people, and consequently for the lower dosages of these drugs used. While CYP2D6 catalyses the metabolism of lipophilic bases only, CYP2C19 is involved in the metabolism of acids (e.g. S-mephenytoin), bases (e.g. imipramine and omeprazole) and neutral drugs (e.g. diazepam). About 3% of Caucasians and 12 to 22% of Orientals are PMs of S-mephenytoin. Polymerase chain reaction-based genotyping techniques recently became available for the two CYP2C19 mutated alleles m1 and m2, which cause no enzyme to be expressed. M1 accounts for about 80% of the mutations responsible for the PM phenotypes in Caucasians, Oriental and Black people. Diazepam is partially demethylated by CYP2C19, and the high frequency of mutated alleles in Orientals is probably the reason why such populations have a slower metabolism and are treated with lower doses of diazepam than Caucasians. Omeprazole is to a major extent hydroxylated by CYP2C19, and there is an approximately 10-fold difference in oral clearance between EMs and PMs of S-mephenytoin. The separation of Caucasians from Orientals is fairly recent in the evolutionary process (40,000 to 60,000 years ago); the separation of Black from Caucasian/Oriental people occurred much earlier, about 150,000 years ago. As pronounced differences have been found between Caucasians and Orientals in the CYP2D6 and CYP2C19 enzymes, it might be expected that Black people will show even greater differences in this respect. Some studies have been performed with Black participants, but the picture is not clear. The mean CYP2D6 activity in Black EMs seems to be lower than that in Caucasian EMs and similar to that of Oriental EMs.(ABSTRACT TRUNCATED AT 400 WORDS)
催化去甲异喹胍/鹰爪豆碱和S-美芬妥因多态性羟基化反应的同工酶分别是细胞色素P450 2D6和P450 2C19（CYP2D6和CYP2C19）。CYP2D6参与几类重要药物的立体特异性代谢，例如抗心律失常药、抗抑郁药和抗精神病药。约7%的高加索人是去甲异喹胍的慢代谢者（PMs），而东方人中只有1%。高加索人PMs中最常见的突变等位基因CYP2D6B在其东方对应人群中几乎不存在。另一方面，东方人广泛代谢者（EMs）中CYP2D6的平均活性低于高加索人EMs。这是由于一种部分缺陷的CYP2D6等位基因频繁分布，导致多达50%的东方等位基因发生脯氨酸34→丝氨酸氨基酸交换。这就是与高加索人相比，东方人对抗抑郁药和抗精神病药代谢较慢，因此使用这些药物剂量较低的分子遗传学基础。虽然CYP2D6仅催化亲脂性碱的代谢，但CYP2C19参与酸（如S-美芬妥因）、碱（如丙咪嗪和奥美拉唑）和中性药物（如地西泮）的代谢。约3%的高加索人和12%至22%的东方人是S-美芬妥因的PMs。基于聚合酶链反应的基因分型技术最近可用于两种导致无酶表达的CYP2C19突变等位基因m1和m2。M1在高加索人、东方人和黑人中导致PM表型的突变中约占80%。地西泮被CYP2C19部分去甲基化，东方人中突变等位基因的高频率可能是这类人群代谢较慢且使用地西泮剂量低于高加索人的原因。奥美拉唑在很大程度上被CYP2C19羟基化，S-美芬妥因的EMs和PMs之间的口服清除率大约相差10倍。在进化过程中，高加索人与东方人的分离相当晚（4万至6万年前）；黑人与高加索人/东方人的分离发生得更早，约15万年前。由于在CYP2D6和CYP2C19酶方面已发现高加索人和东方人之间存在明显差异，预计黑人在这方面会有更大差异。已经对黑人参与者进行了一些研究，但情况尚不清楚。黑人EMs中CYP2D6的平均活性似乎低于高加索人EMs，与东方人EMs相似。（摘要截选至400字）
