DNA HAPLOTYPE-DEPENDENT DIFFERENCES IN THE AMINO-ACID-SEQUENCE OF DEBRISOQUINE 4-HYDROXYLASE (CYP2D6) - EVIDENCE FOR 2 MAJOR ALLOZYMES IN EXTENSIVE METABOLIZERS

The molecular basis for DNA haplotype-dependent debrisoquine 4-hydroxy lase (CYP2D6) expression was explored by sequencing all of the nine ex ons of the CYP2D6 gene. Two distinct exon sequence frameworks of the C YP2D6 gene were found, each associated with specific BamHI-defined DNA haplotypes of the CYP2D cluster. They corresponded to Arg(296)/Cys(29 6) and Ser(486)/Thr(486) amino 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 presume d substrate recognition region and in the vicinity of the heme binding site could be the source of the observed DNA haplotype-dependent vari ation in phenotypic expression.