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 in vivo, we first analysed 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 CYP2D 6 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 hétérozygotes for the haplotype 29-C and a 29 kb haplotype carrying the defective CYP2D6*B allele (haplotype 29-B). These data demonstrate that in vivo the mutation D6-C does not result in an enzyme deficiency severe enough to cause the poor metabolizer phenotype, in contrast to previous expectations resulting from in in vitro data. However, the possibility of a deficiency of the mutant CYP2D6* C protein towards other CYP2D6 substrates cannot be ruled out.
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