FREQUENT DISTRIBUTION OF ULTRARAPID METABOLIZERS OF DEBRISOQUINE IN AN ETHIOPIAN POPULATION CARRYING DUPLICATED AND MULTIDUPLICATED FUNCTIONAL CYP2D6 ALLELES

The debrisoquine hydroxylase (CYP2D6) catalyzes the oxidative metaboli sm of more than 40 different clinically important drugs. The CYP2D6 ge ne is highly polymorphic. Defect alleles, causing the poor metabolizer phenotype, and also alleles with duplicated or multiduplicated active genes, causing ultrarapid metabolism, have been described. In the cur rent investigation, we have evaluated the CYP2D6 phenotype (n = 115) a nd genotype (n = 122) among healthy Ethiopians. Only two subjects (1.8 %) exhibited metabolic reaction (MR) for debrisoquine > 12.6 and were classified as poor metabolizers. A mutation in exon 1 causing a (34)Pr o-->Ser amino acid exchange, typical of the Chinese CYP2D610B (Ch(1)) allele and yielding an unstable enzyme, was present among 16% of the population and the carriers exhibited a high MR (0.9-5.0). Increased M R was also found among 18% of the subjects with a (107)Thr-->Ile mutat ion associated to the CYP2D617 (Z) allele causing diminished activity of CYP2D6 in vivo. Interestingly, 29% of the population investigated carried alleles with duplicated or multiduplicated CYP2D6 genes, indic ative of ultrarapid metabolism. Xbal and EcoRI RFLP analyses identifie d individuals having new alleles with four or five CYP2D62 (L) genes. Subjects with duplicated or multiduplicated CYP2D62 genes exhibited the lowest MR. These results suggest that the Ethiopian population, in comparison to Caucasian, Oriental and other Black populations, is gen etically different with respect to the constitution of the CYP2D locus . The results also show that subjects carrying duplicated or multidupl icated active CYP2D6 genes are very common in certain ethnic groups, i mplicating this issue of potential global importance.