Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene.

A mutant allele of the CYP2D6 gene (CYP2D6* C) characterized by a 3-base-pair deletion in exon 5 (mutation D6-C) and carried by a Xba I 29 kb restriction fragment (haplotype 29-C) was previously presumed to be associated with the debrisoquine poor metabolizer phenotype on the basis of in vitro enzymatic criteria. In order to determine whether D6-C was related to a deficient CYP2D6 activity in vivo, we first analyzed the CYP2D6 gene in the family of a carrier of the haplotype 29-C by combining Xba I-restriction-fragment-length polymorphism analysis and specific CYP2D6 mutation detection by polymerase chain reaction assays. Moreover, each member of the family was phenotyped using debrisoquine as probe drug. Secondly, we used polymerase chain reaction assays to test for the CYP2D6* C mutation DNA samples from 146 unrelated healthy volunteers with the extensive metabolizer phenotype and previously identified as heterozygous carrier of one of the haplotypes known to be associated with the poor metabolizer phenotype. All family members were extensive metabolizers and three were compound heterozygotes for the haplotype 29-C and a 11.5 kb haplotype that has been shown to lack the entire CYP2D6 gene. In addition, two extensive metabolizer individuals among the 146 tested for were compound heterozygotes for the haplotype 29-C and a 29 kb haplotype carrying the defective CYP2D68* B allele (haplotype 29-B).(ABSTRACT TRUNCATED AT 250 WORDS)