Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19.
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)
Bertilsson
L
L
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Sweden.
D000928:Antidepressive Agents / Q000378:metabolism; D014150:Antipsychotic Agents / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism; D005843:Geography; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009853:Omeprazole / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010641:Phenotype; D011110:Polymorphism, Genetic; D044469:Racial Groups; D013379:Substrate Specificity; D044465:White People
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D009853:Omeprazole; D003975:Diazepam