DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers

摘要

The molecular basis for DNA haplotype-dependent debrisoquine 4-hydroxylase (CYP2D6) expression was explored by sequencing all of the nine exons of the CYP2D6 gene. Two distinct exon sequence frameworks of the CYP2D6 gene were found, each associated with specificBamHI-defined DNA haplotypes of the CYP2D cluster. They corresponded to Arg296/Cys296and Ser486/Thr486amino acid polymorphisms in the CYP2D6 enzyme, and occurred in almost equal frequency among the Caucasians examined. These two major allozymes with amino acid differences in the presumed substrate recognition region and in the vicinity of the heme binding site could be the source of the observed DNA haplotype-dependent variation in phenotypic expression.