The metabolism and activation of 15,16-dihydrocyclopental[a]phenanthren-17-one by cytochrome P-450 proteins

Abstract

The in vitro metabolism and activation to mutagens of 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) were investigated using hepatic preparations from rats pretreated with prototype inducers of the cytochrome P-450-dependent mixed-function oxidases. Aroclor 1254-induced microsomes were the most effective metabolisers of this compound, the major metabolites being oxidation products of the bay region A ring. To a lesser extent hydroxylation of the non-aromatic D ring occurred, the products being the 15- and 16-hydroxyderivatives. Oxidation of the A ring was also achieved with microsomes from benzo[a]pyrene-treated rats but not with those from rats treated with clofibrate, phenobarbitone, isoniazid, dexamethasone and CPP-17-one itself, where the metabolites were primarily the oxidation products of the D ring. When CPP-17-one was used as a promutagen in the Ames test, only microsomes from Aroclor 1254-treated rats could elicit a positive mutagenic response. When 3,4-dihydrodihydroxy-CPP-17-one, the precursor of the ultimate mutagen, was used as the promutagen, a positive response was observed with microsomes from Aroclor 1254- and benzo[a]pyrene-treated rats. It is concluded that (a) CPP-17-one is metabolised through oxidation of the D ring to produce non-mutagenic products and only through A ring oxidation mutagens are produced, (b) only the CYP1A (cytochrome P-450 family 1, subfamily A) family (induced by benzo[a]pyrene and Aroclor 1254) could oxidise the A ring, and (c) Aroclor 1254-induced hepatic microsomes are the most effective catalysts of the metabolism and activation of CPP-17-one because, in addition to the high CYP1A activity, they are also characterised by high levels of microsomal epoxide hydrolase.