PHENOTYPING AND GENOTYPING OF S-MEPHENYTOIN HYDROXYLASE (CYTOCHROME-P450 2C19) IN A SHONA POPULATION OF ZIMBABWE

The S-mephenytoin hydroxylase has recently been identified as cytochro me P450 2C19 (CYP2C19), This enzyme metabolizes mephenytoin, diazepam, omeprazole, and citalopram and has been shown to be polymorphically d istributed One clinical implication of CYP2C19-dependent drug metaboli sm for persons who reside in tropical regions is in the use of the ant imalarial drug chloroguanide hydrochloride which is apparently biotran sformed to its active metabolite by this isozyme, In this investigatio n we studied mephenytoin metabolism in 103 black Zimbabwean Shona subj ects, Pour were identified as poor metabolizers (4%), This prevalence is comparable to that in white subjects (2% to 5%) but lower than the 15% to 20% incidence of poor metabolizers among Oriental subjects, Of the subjects phenotyped, 84 were genotyped for the G-->A mutation in e xon 5 of CYP2C19, which creates a cryptic splice site, causing the pro duction of a nonfunctional protein, Three of the four poor metabolizer s were homozygous for this mutation, whereas the fourth one was hetero zygous, The G-->A mutation has been shown to predict the incidence mor e than 60% of poor metabolizers among white subjects and Japanese subj ects, and in the current investigation we also obtained a similar rela tionship in the black population.