Metabolism of DHEA by cytochromes P450 in rat and human liver microsomal fractions

Administration of dehydroepiandrosterone (DHEA) to rodents produces many un ique biological responses, some of which may be due to metabolism of DHEA t o more biologically active products. In the current study, DHEA metabolism was studied using human and rat liver microsomal fractions. in both species , DHEA was extensively metabolized to multiple products; formation of these products was potently inhibited in both species by miconazole, demonstrati ng a principal role for cytochrome P450, In the rat, use of P450 form-selec tive inhibitors suggested the participation of P4501A and 3A forms in DHEA metabolism. Human liver samples displayed interindividual differences in th at one of five subjects metabolized DHEA to a much greater extent than the others, This difference correlated with the level of P4503A activity presen t in the human liver samples. For one subject, troleandomycin inhibited hep atic microsomal metabolism of DHEA by 78%, compared to 81% inhibition by mi conazole, suggesting the importance of P4503A in these reactions. Form-sele ctive inhibitors of P4502D6 and P4502E1 had a modest inhibitory effect, sug gesting that these forms may also contribute to metabolism of DHEA in human s. Metabolites identified by LC-MS in both species included 16 alpha -hydro xy-DHEA, 7 alpha -hydroxy-DHEA, and 7-oxo-DHEA, While 16 alpha -hydroxy-DHE A appeared to be the major metabolite produced in rat, the major metabolite produced in humans was a mono-hydroxylated DHEA species, whose position of hydroxylation is unknown. (C) 2001 Academic Press.