PHENOTYPE AND GENOTYPE ANALYSIS OF DEBRISOQUINE HYDROXYLASE (CYP2D6) IN A BLACK ZIMBABWEAN POPULATION - REDUCED ENZYME-ACTIVITY AND EVALUATION OF METABOLIC CORRELATION OF CYP2D6

Objective: Debrisoquine hydroxylase (CYP2D6) is responsible for the ox idative metabolism of many clinically used drugs. Since this enzyme ha s been poorly studied in the southern part of Africa, we examined the CYP2D6 phenotypes and genotypes in 103 unrelated black Zimbabweans, Me thods: Phenotyping for CYP2D6 activity was done using debrisoquine and metoprolol as probe drugs by measuring the urinary metabolic ratio (M R) of parent drug to metabolite concentration ratios. Genotyping was d one using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), single-strand conformation polymorphism (SSCP) a nd sequencing analyses with respect to CYP2D6 variants of interest. Re sults and conclusion: Phenotyping with debrisoquine revealed two poor metabolisers (PMs), whereas 5 subjects out of 94 were PMs using metopr olol as probe drug. Genotypes predictive of the poor metaboliser statu s were observed for the two subjects who were PMs with both probe drug s, whereas no mutations could explain the PM phenotype for metoprolol among the three remaining subjects, a fact possibly explained by lack of compliance in metoprolol intake. There was a moderate correlation o f 0.67 between the debrisoquine and metoprolol metabolic ratios in the 89 subjects who were extensive metabolisers for both probe drugs. The median values for the metabolic ratios for debrisoquine and metoprolo l as probe drugs were 1.00 and 1.35, respectively, which are higher th an those observed in Caucasian populations, This is indicative of a de creased capacity for metabolism of CYP2D6 substrates by Zimbabweans co mpared to Caucasians. Evaluation of the DNA samples for the known alle lic variants CYP2D6A, CYP2D6B, CYP2D6C, CYP2D6D or CYP2D6Ch(1) yielded no explanation for these results.