DNA HAPLOTYPE DEPENDENCY OF DEBRISOQUINE 4-HYDROXYLASE (CYP2D6) EXPRESSION AMONG EXTENSIVE METABOLIZERS

Deficient debrisoquine/sparteine type oxidation is inherited as an aut osomal recessive trait. Of all Caucasians, 5-10% are poor metabolisers , due to the absence of cytochrome P4502D6. Extensive metabolisers (EM s) exhibit highly variable metabolic activity. We investigated the rel ationship between CYP2D6 activity and genotypes of the CYP2D locus in a large set of French Caucasian families. Genotypes concern both commo n mutations affecting the enzyme activity and linked BamHI polymorphis ms of the locus. We found, like other authors, that in EMs part of the heterogeneity is explained by a subgroup of individuals heterozygous for a mutant allele. However, a second level of heterogeneity was dete cted among individuals not carrying mutations, and this was related to a polymorphic BamHI-defined DNA haplotype. Different combinations of haplotypes are associated with differences in CYP2D6 metabolic activit y. This finding might help to clarify the conflicting data on the rela tion between CYP2D6 activity and susceptibility to lung cancer.