Deficient hydroxylation of debrlsoquine Is an autosomal recessive trait that affects =7% of the Caucasian population. These individuals (poor metabolizers) carry deficient CYP2D6 gene variants and have an impaired metabolsm of several commonly used drugs. The opposite phenomenon also exists, and certain individuals metabolize the drugs very rapidly, resulting in subtherapeutic plasma concentrations at normal doses. In the present study, we have investigated the molecular genetic basis for ultrarapid metabolism of debrisoquine. Restriction fragment length polymorphism analysis of the CYP2D locus in two families with very rapid metabolism of debrisoquine [metabolic ratio (MR) for debrisoquine = 0.01-0.11 revealed the variant CYP2D6 gene CYP2D6L. EcoRI RFLP and Xba I pulsed-field gel electrophoresis analyses showed that this gene had been amplifled 12-fold in three members (father and his two children) of one ofthe families, and two copies were present among members of the other family. The CYP2D6L gene had an open reading frame and carried two mutations causing amino acid substitutions: one in exon 6, yielding an Arg-296 --Cys exchange and one in exon 9 causing Ser-486 --Thr. The MR of subjects carrying one copy of the CYP2D6L gene did not signicantiy differ from that of those with the wild-ype gene, indicating that the structural alterations were not of importance for the catalytic properties of the gene product. Examination of the MR among subjects carrying wild-type CYP2D6, CYP2D6L, or deficient alleles revealed a relationship between the number of active genes and MR. The data show the principle of inherited amplification of an active gene. Furthermore, the finding of a specific haplotype with two or more active CYP2D6 genes allows genotyping for ultrarapid drug metabolizers. This genotyping could be of predictive value for individualized and more efficient drug therapy.

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