Identification of genetic differences in drug metabolism: Prediction of individual risk of toxicity or cancer

Authors


Abstract

These two reports describe recombinant DNA tests that can identify individuals having a defect in the cytochrome P450IID6 (CYP2D6)-mediated oxidative metabolism of debrisoquine and more than two dozen other drugs that are commonly prescribed. The poor metabolizer (PM), representing 5% to 10% of the northern European white population is homozygous for an autosomal recessive trait. Compared with the extensive metabolizer (EM) phenotype, the PM individual is more prone to toxicity caused by some of these drugs. Curiously, the PM phenotype appears to be associated with a lower risk of lung and bladder cancer.

Gough and coworkers propose that the primary gene defect associated with the CYP2D6 polymorphism appears to be a G to A transition mutation affecting the splice junction of intron 3/exon 4 of the CYP2D6 gene. They offer a polymerase chain reaction (PCR) amplification method for diagnosing three variant alleles and claim to have predicted the phenotype of all normal and 34 of 42 (81%) PM individuals. Based on the known frequencies of those variant alleles detectable by this method, however, the assay would be expected to predict less than 60% of PM patients. Heim and Meyer, on the other hand, have combined allelespecific PCR with restriction fragment length polymorphism (RFLP) patterns to identify more than 95% of all mutant alleles, suggesting that their assay would accurately predict more than 90% of all PM individuals. Using this latter assay or a similar test with further improvements, especially in combination with family studies, it should soon be possible for the physician to determine the CYP2D6 phenotype of the patient, thereby avoiding toxic drug overdoses.

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