A NOVEL MUTANT VARIANT OF THE CYP2D6 GENE (CYP2D6-ASTERISK-17) COMMONIN A BLACK-AFRICAN POPULATION - ASSOCIATION WITH DIMINISHED DEBRISOQUINE HYDROXYLASE-ACTIVITY

1 The debrisoquine hydroxylase (CYP2D6) is polymorphically distributed . Not only are there differences in the proportions of extensive metab olisers to poor metabolisers in various ethnic groups, but there are a lso pronounced variations in the metabolic capacity among those classi fied as extensive metabolisers. 2 The mean debrisoquine metabolic rati o of Caucasian extensive metabolisers is lower than that for a number of African populations. In the present study, we have searched for nov el CYP2D6 mutations to explain the diminished enzyme activity in Afric an populations. 3 Three Zimbabwean Shona subjects with EM phenotypes ( metabolic ratios for debrisoquine of 0.4, 1.5 and 10.5 respectively) w ere selected and the open reading frame of the CYP2D6 gene of each was sequenced. 4 The subject with metabolic ratio of 10.5 was found to be homozygous for an allele with a nucleotide exchange in exon 2, C-1111 -->T causing a (107)Thr-->Ile amino acid exchange in a conserved regio n of the enzyme. In addition, he was homozygous for the C-2938-->T and (4268)G-->C mutations causing (296)Arg-->Ser and (486)Ser-->Thr amino acid substitution found in the CYP2D62 allele. 5 Seventy-six Zimbabw ean Shona subjects were subsequently genotyped for the C-1111-->T muta tion and for the intron 1 gene conversion present in the CYP2D62 gene . The C-1111-->T mutation was found at an allele frequency of 34% and was only present in alleles carrying the gene conversion in intron 1 i ndicative for the CYP2D62 gene. 6 This allele (CYP2D6*17), containing the C-1111-->T, C-2938-->T and (4268)G-->C mutations, was found to be strongly associated with lower capacity for debrisoquine hydroxylatio n. We therefore postulate that the CYP2D617 allele might contribute t o the molecular basis of the previously established diminished debriso quine hydroxylase activity in African Bantu populations.