title: Cytochrome P450-dependent metabolism and mutagenicity of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and their implications in its carcinogenicity.
abstract: Methylation of the non-carcinogen 15,16-dihydrocyclopenta[a]phenanthren-17-one (CPP-17-one) at the bay region to form 11-CH3-CPP-17-one confers carcinogenic potential. In the present study we have investigated the in vitro metabolism and mutagenicity of the methylated compound by hepatic microsomal preparations from rats pretreated with various prototype inducers of cytochrome P450 proteins in order to provide a rationale for this marked difference in carcinogenic activity. The most effective metabolism of 11-CH3-CPP-17-one occurred in the presence of Aroclor 1254-induced microsomes, the principal metabolites being oxidative products of the A- and D-rings and of the methyl substituent. When benzo[a]pyrene-induced microsomes served as the metabolising system, the major A-ring metabolite was the 3,4-diol. A similar metabolic pattern was seen with microsomes from rats treated with 11-CH3-CPP-one itself, but the overall effect of metabolism was lower than that observed with benzo[a]pyrene-treated microsomes but higher than that of control animals. In contrast, microsomes from rats treated with clofibrate, dexamethasone, isoniazid and phenobarbitone failed to enhance the metabolism of 11-CH3-CPP-17-one when compared with control microsomes and the metabolites reflected primarily oxidation of the D-ring. When 11-CH3-CPP-17-one was employed as a promutagen in the Ames test, a mutagenic response was evident only in the presence of microsomes from benzo[a]pyrene-induced rats, but induction with phenobarbitone, isoniazid, dexamethasone, clofibrate and the compound itself, failed to elicit a positive mutagenic response. When 3,4-dihydroxy-11-CH3-CPP-17-one served as the promutagen, a mutagenic response was observed in the presence of benzo[a]pyrene-induced and, to a lesser extent, 11-CH3-CPP-17-one-induced microsomes. Treatment of rats with 11-CH3-CPP-17-one caused a marked increase in the O-deethylation of ethoxyresorufin and, to a much lesser extent in epoxide hydrolase activity. It is concluded that (i) 11-CH3CPP-17-one is an inducer of the CYP1 family; (ii) under the present experimental conditions only the CYP1 family can oxidise the A-ring to form the 3,4-dihydroxy-11-CH3-CPP-17-one, the precursor of the ultimate carcinogen and (iii) only the CYP1 family oxidizes the diol to generate the ultimate carcinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Division of Toxicology, School of Biological Sciences, University of Surrey, Guildford, UK.
authors.forename: G W
authors.initials: GW
authors.lastname: Boyd
authors.forename: R J
authors.initials: RJ
authors.lastname: Young
authors.forename: R G
authors.initials: RG
authors.lastname: Harvey
authors.forename: M M
authors.initials: MM
authors.lastname: Coombs
authors.forename: C
authors.initials: C
authors.lastname: Ioannides
mesh_terms: D000818:Animals; D001140:Aroclors; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006067:Gonanes / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet
chemical_list: D001140:Aroclors; D006067:Gonanes; D020111:Chlorodiphenyl (54% Chlorine); C011770:15,16-dihydrocyclopenta(a)phenanthren-17-one; D003577:Cytochrome P-450 Enzyme System