A comparative examination of the in vitro metabolism of five cyclopenta[a]phenanthrenes of varying carcinogenic potential.
Metabolites of 15,16-dihydrocyclopenta[a]phenanthren-17-one and its 1- and 12-methyl homologues (all non-carcinogens) along with those from the 11-methyl and 11,12-dimethyl-17-ketones (carcinogens), produced in vitro by hepatic microsomes from methylcholanthrene induced rats, were separated by reverse phase h.p.l.c. Identifications of individual metabolites were based upon elution times, u.v. spectra, and in some cases by mass spectrometry, circular dichroism, and identity with synthetic derivatives. All five compounds were biologically oxidised at their terminal A and D rings to yield 1,2-dihydrodiols and 15- and 16- ols; with the exception of the 1-methyl compound, all also gave similar amounts of 3,4-dihydrodiols. The 1-methyl compound by contrast failed to produce this metabolite, furnishing instead the 4-phenol and five other, probably related phenolic derivatives. Previous work has established that for the 11-methyl-17-ketone, the 3,4-dihydrodiol is the proximate carcinogen. Thus, whereas lack of biological activity with the 1-methyl compound can be ascribed to its failure to produce a 3,4-dihydrodiol, in the case of the unsubstituted parent ketone and its 12-methyl derivative other determining factors must come into play.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D006067:Gonanes / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
D002273:Carcinogens; D006067:Gonanes