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.
Boyd, G., Young, R. J., Harvey, R. G., Coombs, M. M., & Ioannides, C. (1993). The metabolism and activation of 15,16-dihydrocyclopenta[a]phenanthren-17-one by cytochrome P-450 proteins. European Journal of Pharmacology, 228(5-6), 275-282. https://doi.org/10.1016/0926-6917(93)90061-T