ULTRARAPID HYDROXYLATION OF DEBRISOQUINE IN A SWEDISH POPULATION - ANALYSIS OF THE MOLECULAR-GENETIC BASIS

Hydroxylation of debrisoquine, catalyzed by the cytochrome P450 CYP2D6 exhibits genetic polymorphism, with large interindividual differences in metabolic capacity. About 7% of Caucasians carry deficient CYP2D6 alleles and lack the CYP2D6 enzyme (poor metabolizers). We have shown in two Swedish families, individuals carrying duplicated or amplified functional CYP2D6L-genes (CYP2D6L2), causing the opposite phenomenon, ultrarapid metabolism of debrisoquine. in the present study, the occur rence of extra copies of CYP2D6L-alleles was studied in relation to de brisoquine metabolic ratio (MR) in 270 Swedish Caucasians including 64 selected subjects with very rapid metabolism (MR less than or equal t o 0.2). Thirteen of the 64 subjects carried a duplicated CYP2D6-gene a s identified by EcoRI and Xbal restriction fragment length polymorphis m and allele-specific polymerase chain reaction-amplification of genom ic DNA. A new allele with three active CYP2D6L-genes was identified, c haracterized by an Xbal 54 kilobase fragment. This indicates a prefere nce of the CYP2D6L-gene to be amplified compared to other CYP2D6 genes . Only one subject with an MR higher than 0.2 carried the duplicated C YP2D6L-allele, also being heterozygous for the defect CYP2D6B-allele, The overall frequency of the duplicated/amplified CYP2D6-allele was ab out 1%, and was present in 40% of subjects with MRs less than or equal to 0.1, Thus, other variant CYP2D6-genes may exist that cause increas ed CYP2D6 activity. In conclusion, a haplotype with duplicated or ampl ified functional CYP2D6 genes predicts, with high accuracy, ultrarapid metabolism of debrisoquine. Genotyping for this CYP2D locus variant m ight be of value in patients not responding to generally recommended d oses of CYP2D6 substrates, to distinguish between high metabolic capac ity and noncompliance.