Faculty Collaboration Database

Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity. Pharmacogenetics 2001 Jul;11(5):417-27

Date

07/27/2001

Pubmed ID

11470994

DOI

10.1097/00008571-200107000-00005

Scopus ID

2-s2.0-0034743396 (requires institutional sign-in at Scopus site)   75 Citations

Abstract

Debrisoquine metabolism among Tanzanians has been found to be slower than expected from the CYP2D6 genotype. In order to evaluate any genetic explanation, the coding sequence and intron-exon boundaries of the CYP2D6 gene from three Black Tanzanian volunteers with a CYP2D6*1/*1 or CYP2D6*2/*2 genotype and debrisoquine metabolic ratios (MRs) > 1 were fully sequenced to screen for new mutations. Two functional mutations, G1747 to A (causing V136I) and G3271 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 frequency of 20%. The CYP2D6*29 allele, having also the mutations of the CYP2D6*2 allele, was subsequently expressed in yeast and mammalian COS-1 cells. No differences were seen with respect to the affinity (Km) or maximal velocity (Vmax) of the CYP2D6 substrate bufuralol between the wild-type and mutant when expression was carried out in yeast cells. By contrast, the 1'-hydroxybufuralol catalytic activity of the mutant expressed in COS-1 cells was only 26% of the wild-type (P < 0.01; Mann-Whitney U-test) and its debrisoquine hydroxylation activity was 63% of that of CYP2D6.1. The single mutants V136I and V338M had reduced capacity for bufuralol hydroxylation, but the effect was even stronger when both mutations were present together as in CYP2D6.29. Analysis of the distribution of CYP2D6*29 in subjects phenotyped for debrisoquine revealed that this allele significantly causes a reduction in the rate of debrisoquine hydroxylation in vivo. The results indicate the common existence in Tanzanians of a variant CYP2D6 form with different substrate specificity as compared to the wild-type form of the enzyme causing reduced capacity for debrisoquine metabolism.

Author List

Wennerholm A, Johansson I, Hidestrand M, Bertilsson L, Gustafsson LL, Ingelman-Sundberg M

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
COS Cells
Catalysis
Cytochrome P-450 CYP2D6
DNA Primers
Humans
Mutagenesis, Site-Directed
Tanzania