Study of the association between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug and chemical induced idiosyncratic aplastic anaemia

A genetic susceptibility to drug or chemical toxicity may provide a basis f or an increased risk of idiosyncratic aplastic anaemia (AA). The cytochrome P450 enzymes are responsible for the metabolism of many drugs, some of whi ch have been linked to AA. Mutations in the cytochrome P450 CYP2D6 gene res ult in absent or impaired enzyme activity in about 7% of Caucasians, wherea s a specific mutation in the 5'-regulatory region of the CYP2E1 gene causes overexpression of the gene. We evaluated the frequency of allelic variants of CYP2D6 and CYP2E1 using allele-specific PCR amplification and restricti on enzyme analysis of blood mononuclear cell DNA among 54 Caucasian AA pati ents. CYP2D6 and CYP2E1 were chosen because of the link between AA and the antipsychotic drug remoxipride (CYP2D6 substrate) and benzene (CYP2E1 subst rate), respectively Results were compared with 53 controls matched for age, sex and ethnicity The percentage of AA patients homozygous for the CYP2D6* 3, CYP2D6*4 alleles (poor metabolizer phenotype) and the CYP2E1 mutant alle le (overexpression) was 0%, 4% and 0%, respectively, and the percentage of heterozygotes was 2%, 28% and 15%, respectively. For normal controls the co rresponding results for homozygous mutants were 0%, 4% and 0% and for heter ozygotes 4%, 25% and 6%, respectively. We concluded that there were no majo r differences in the frequencies of the genetic polymorphisms between this series of AA patients and controls, but due to the low number of cases with the poor metabolizer phenotype and those with a history of drug exposure, the power of the study was too low to disprove an interaction.