A number of genetic polymorphisms in drug oxidation have been described in humans. These are manifested by the ability of certain individuals to metabolize a series of drugs. The most extensively studied is the debrisoquine polymorphism in which from 5 to 10% of Caucasians cannot metabolize debrisoquine, and a growing list of drugs. The mechanism of this polymorphism is mutations in a specific P450 gene, the CYP2D6 gene. The CYP2D gene subfamily is found to contain at least three highly related genes. In addition to CYP2D6, the CYP2D7 gene, that appears to be inactive, and a CYP2D8P, which is a pseudogene, were found. Gene conversions have occurred among these P450 genes. The availability of the complete sequences of these genes will allow the PCR-based test to be carried out to diagnose mutant CYP2D6 genes to predict those individuals susceptible to drug toxicities. A rat model has also been developed for the human debrisoquine polymorphism. To determine the complexity of the CYP2D locus in this species, isolation and sequencing of genomic clones were carried out. The rat possesses five genes; two, CYP2DI and CYP2D5 display over 95% sequence similarity, while the remaining three genes share between 79 to 84% sequence similarity. Gene conversions have occurred among the rat CYP2D genes, resulting in virtually absolute sequence identity among all genes within a region encoding the heme-binding pocket.
