Identification of 7,12-dimethylbenz(a)anthracene metabolites that lead to mutagenesis in mammalian cells

Journal Article · Thu Feb 01 04:00:00 UTC 1979 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.76.2.862· OSTI ID:5059510

Huberman, E ^[1]; Chou, M W; Yang, S K

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1. Oak Ridge National Lab., TN

The mutagenicity of 7,12-dimethylbenz(a)-anthracene (DMBA) and 11 of its metabolites was tested with Chinese hamster V79 cells. Mutations were characterized by resistance to ouabain and 6-thioguanine. None of the tested metabolites was mutagenic in V79 cells, which do not metabolize polycyclic aromatic hydrocarbons. DMBA, 7-hydroxymethyl-12-methylbenz(a)anthracene, 7-methyl-12-hydroxymethylbenz(a)anthracene, and their trans-3,4-diols were mutagenic for both genetic markers, and the mutagenic response increased as a function of the hydrocarbon dose. All other metabolites were either inactive or showed up to a 4-fold higher mutation frequency than the untreated V79 cells for ouabain and 6-thioguanine resistance. The DMBA-trans-3,4-diol was the only metabolite that was more active than DMBA itself; at 0.05 ..mu..M it was 6 to 8 times more active than DMBA.in inducing both ouabain and 6-thioguanine resistance. This diol was mutagenic at a dose as low as 0.01 ..mu..M. Mutagenesis by DMBA and the trans-3,4-diols was inhibited by 7,8-benzoflavone, an inhibitor of mixed-function oxidases. Analysis of DMBA metabolism in intact golden hamster cells indicated that DMBA-trans-3,4-diol is one of the major metabolites produced. Our results therefore suggest that DMBA-trans-3,4-diol may be metabolized to a diol-epoxide, presumably the trans-3,4-diol-1,2-epoxide, which may be a major reactive metabolite responsible for DMBA mutagenicity in mammalian cells.

• DOE Contract Number: W-7405-ENG-26
• OSTI ID: 5059510
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 76:2; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
560301* -- Chemicals Metabolism & Toxicology-- Cells-- (-1987)
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALCOHOLS
ANIMALS
AROMATICS
BIOCHEMICAL REACTION KINETICS
CELL CULTURES
CONDENSED AROMATICS
DIMETHYLBENZANTHRACENE
DOSE-RESPONSE RELATIONSHIPS
EPOXIDES
GLYCOLS
HAMSTERS
HYDROXY COMPOUNDS
KINETICS
MAMMALS
METABOLISM
METABOLITES
MUTAGEN SCREENING
MUTAGENESIS
MUTATION FREQUENCY
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
REACTION KINETICS
RODENTS
SCREENING
TOXICITY
VERTEBRATES