SPECIES VARIATION IN THE METABOLISM OF 6-DIHYDRO-11-METHYLCYCLOPENTA[A]PHENANTHREN-17-ONE TO ITS 3,4-DIHYDRODIOL, THE PROXIMATE CARCINOGEN

The title compound is a strong carcinogen, similar in potency to benzo [a]pyrene in mouse skin assay. This paper describes a comparison of it s in vitro metabolism by hepatic microsomal preparations from mouse, r at, rabbit, hamster, dog, monkey and man. Metabolites were isolated by preparative high pressure liquid chromatography from the ethyl acetat e extractable material and their structures tentatively assigned on th e basis of their retention times and ultraviolet spectra, when possibl e by direct comparison with authentic synthetic specimens. Mass spectr ometry was then used to confirm these assignments. All these animals p roduce the same range of metabolites derived exclusively from oxidatio n at the benzoring A, the five-membered ring D, and at the 11-methyl g roup. However, the amounts of individual metabolites varied substantia lly. In particular all the animals yielded the proximate carcinogen 4, 15,16-tetrahydrocyclopenta[a]phenanthren-17-one, from which it is reas oned that all might be susceptible to its carcinogenic action. A ratio nalization for the observed distribution of the metabolites is propose d on the basis of a molecular model of the active site of cytochrome P 450 1A1, the oxidative enzyme involved.