Identification of 7,12-dimethylbenz(a)anthracene metabolites that lead to mutagenesis in mammalian cells
- 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), Vol. 76:2
- Country of Publication:
- United States
- Language:
- English
Similar Records
Metabolism of benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene in cultured human fetal aortic smooth muscle cells
Stereoselective fungal metabolism of 7,12-dimethylbenz(a)anthracene: identification and enantiomeric resolution of a K-region dihydrodiol
Related Subjects
59 BASIC BIOLOGICAL SCIENCES
DIMETHYLBENZANTHRACENE
METABOLISM
METABOLITES
TOXICITY
BIOCHEMICAL REACTION KINETICS
CELL CULTURES
DOSE-RESPONSE RELATIONSHIPS
EPOXIDES
GLYCOLS
HAMSTERS
MUTAGEN SCREENING
MUTAGENESIS
MUTATION FREQUENCY
ALCOHOLS
ANIMALS
AROMATICS
CONDENSED AROMATICS
HYDROXY COMPOUNDS
KINETICS
MAMMALS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
REACTION KINETICS
RODENTS
SCREENING
VERTEBRATES
560301* - Chemicals Metabolism & Toxicology- Cells- (-1987)
550200 - Biochemistry