Species variation in the metabolism of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one to its 3,4-dihydrodiol, the proximate carcinogen

Gary Boyd, Maurice M Coombs, Costas Ioannides, David FV Lewis, J Snelling, A Tsakalof

Research output: Contribution to journalArticle

Abstract

The title compound is a strong carcinogen, similar in potency to benzo[a]pyrene in mouse skin assay. This paper describes a comparison of its in vitro metabolism by hepatic microsomal preparations from mouse, rat, rabbit, hamster, dog, monkey and man. Metabolites were isolated by preparative high pressure liquid chromatography from the ethyl acetate extractable material and their structures tentatively assigned on the basis of their retention times and ultraviolet spectra, when possible by direct comparison with authentic synthetic specimens. Mass spectrometry was then used to confirm these assignments. All these animals produce the same range of metabolites derived exclusively from oxidation at the benzoring A, the five-membered ring D, and at the 11-methyl group. However, the amounts of individual metabolites varied substantially. In particular all the animals yielded the proximate carcinogen 3,4-dihydroxy-11-methyl-3,4,15,16- tetrahydrocyclopenta[a]phenanthren-17-one, from which it is reasoned that all might be susceptible to its carcinogenic action. A rationalization for the observed distribution of the metabolites is proposed on the basis of a molecular model of the active site of cytochrome P450 1A1, the oxidative enzyme involved.
Original languageEnglish
Pages (from-to)2351-2355
JournalCarcinogenesis
Volume16
Issue number10
DOIs
Publication statusPublished - Oct 1995
Externally publishedYes

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Carcinogens
Molecular Models
Benzo(a)pyrene
Cricetinae
Cytochrome P-450 Enzyme System
Haplorhini
Mass Spectrometry
Catalytic Domain
High Pressure Liquid Chromatography
Dogs
Rabbits
Skin
Liver
Enzymes
trans-1,2-dihydro-1,2-naphthalenediol
15,16-dihydro-11-methylcyclopenta(a)phenanthren-17-one
ethyl acetate
In Vitro Techniques

Cite this

Boyd, Gary ; Coombs, Maurice M ; Ioannides, Costas ; Lewis, David FV ; Snelling, J ; Tsakalof, A. / Species variation in the metabolism of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one to its 3,4-dihydrodiol, the proximate carcinogen. In: Carcinogenesis. 1995 ; Vol. 16, No. 10. pp. 2351-2355.
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Species variation in the metabolism of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one to its 3,4-dihydrodiol, the proximate carcinogen. / Boyd, Gary; Coombs, Maurice M; Ioannides, Costas; Lewis, David FV; Snelling, J; Tsakalof, A.

In: Carcinogenesis, Vol. 16, No. 10, 10.1995, p. 2351-2355.

Research output: Contribution to journalArticle

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T1 - Species variation in the metabolism of 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one to its 3,4-dihydrodiol, the proximate carcinogen

AU - Boyd, Gary

AU - Coombs, Maurice M

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AU - Lewis, David FV

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AU - Tsakalof, A

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AB - The title compound is a strong carcinogen, similar in potency to benzo[a]pyrene in mouse skin assay. This paper describes a comparison of its in vitro metabolism by hepatic microsomal preparations from mouse, rat, rabbit, hamster, dog, monkey and man. Metabolites were isolated by preparative high pressure liquid chromatography from the ethyl acetate extractable material and their structures tentatively assigned on the basis of their retention times and ultraviolet spectra, when possible by direct comparison with authentic synthetic specimens. Mass spectrometry was then used to confirm these assignments. All these animals produce the same range of metabolites derived exclusively from oxidation at the benzoring A, the five-membered ring D, and at the 11-methyl group. However, the amounts of individual metabolites varied substantially. In particular all the animals yielded the proximate carcinogen 3,4-dihydroxy-11-methyl-3,4,15,16- tetrahydrocyclopenta[a]phenanthren-17-one, from which it is reasoned that all might be susceptible to its carcinogenic action. A rationalization for the observed distribution of the metabolites is proposed on the basis of a molecular model of the active site of cytochrome P450 1A1, the oxidative enzyme involved.

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