Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis.

摘要: Hydroxylation of debrisoquine, catalyzed by the cytochrome P450 CYP2D6 exhibits genetic polymorphism, with large inter-individual differences in metabolic capacity. About 7% Caucasians carry deficient alleles and lack enzyme (poor metabolizers). We have shown two Swedish families, individuals carrying duplicated or amplified functional CYP2D6L-genes (CYP2D6L2), causing opposite phenomenon, ultrarapid metabolism debrisoquine. In present study, occurrence extra copies CYP2D6L-alleles was studied relation to debrisoquine ratio (MR) 270 including 64 selected subjects very rapid (MR < = 0.2). Thirteen carried a CYP2D6-gene as identified EcoRI XbaI restriction fragment length polymorphism allele-specific polymerase chain reaction-amplification genomic DNA. A new allele three active identified, characterized an 54 kilobase fragment. This indicates preference CYP2D6L-gene be compared other genes. Only one subject MR higher than 0.2 CYP2D6L-allele, also being heterozygous for defect CYP2D6B-allele. The overall frequency duplicated/amplified CYP2D6-allele about 1%, 40% MRs 0.1. Thus, variant CYP2D6-genes may exist that cause increased activity. conclusion, haplotype genes predicts, high accuracy, Genotyping this CYP2D locus might value patients not responding generally recommended doses substrates, distinguish between capacity noncompliance.