Characterization of the CYP2D6*29 allele commonly present in a blade Tanzanian population causing reduced catalytic activity

Debrisoquine metabolism among Tanzanians has been found to be slower than e xpected from the CYP2D6 genotype. in order to evaluate any genetic explanat ion, the coding sequence and intron-exon boundaries of the CYP2D6 gene from three Black Tanzanian volunteers with a CYP2D6*/*1 or CYP2D6*2/*2 genotype and debrisoquine metabolic ratios (MRs)>1 were fully sequenced to screen f or new mutations. Two functional mutations, G(1747) to A (causing V136I) an d G(3271) to A (causing V338M), were identified in the CYP2D6*2/*2 sample. Thirty-six subjects (34%) out of a total 106 subjects were heterozygous and three subjects (3%) were homozygous for the allele, yielding an allele fre quency of 20%, The CYP2D6*29 allele, having also the mutations of the CYP2D 6*2 allele, was subsequently expressed in yeast and mammalian COS-I cells, No differences were seen with respect to the affinity (K-m) or maximal velo city (V-max) of the CYP2D6 substrate bufuralol between the wild-type and mu tant when expression was carried out in yeast cells, By contrast, the 1'-hy droxybufuralol catalytic activity of the mutant expressed in COS-I cells wa s only 26% of the wild-type (P<0.01; Mann-Whitney U-test) and its debrisoqu ine hydroxylation activity was 63% of that of CYP2D6.1. The single mutants V136I and V338M had reduced capacity for bufuralol hydroxylation, but the e ffect was even stronger when both mutations were present together as in CYP 2D6.29. Analysis of the distribution of CYP2D6*29 in subjects phenotyped fo r debrisoquine revealed that this allele significantly causes a reduction i n the rate of debrisoquine hydroxylation in vivo, The results indicate the common existence in Tanzanians of a variant CYP2D6 form with different subs trate specificity as compared to the wild-type form of the enzyme causing r educed capacity for debrisoquine metabolism, Pharmacogenetics 11:417-427 (C ) 2001 Lippincott Williams & Wilkins.