Journal Article

Influence of β-Naphthoflavone on 7,12-Dimethylbenz(a)anthracene Metabolism, DNA Adduction, and Tumorigenicity in Rainbow Trout

Tracy L. Weimer, Ashok P. Reddy, Ulrich Harttig, David Alexander, S. Craig Stamm, Michael R. Miller, William Baird, Jerry Hendricks and George Bailey

in Toxicological Sciences

Volume 57, issue 2, pages 217-228
Published in print October 2000 | ISSN: 1096-6080
Published online October 2000 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/57.2.217
Influence of β-Naphthoflavone on 7,12-Dimethylbenz(a)anthracene Metabolism, DNA Adduction, and Tumorigenicity in Rainbow Trout

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Metabolism, DNA adduction, and tumor induction by 7,12-dimethylbenz(a)anthracene (DMBA) were examined in cultured trout liver cells and in vivo in trout. Modulating CYP1A1 activity indicated this enzyme plays a significant role in metabolizing DMBA to water-soluble compounds in isolated trout liver cells. The major DMBA metabolites identified in trout liver cells were 10-, 11-, 8,9-, and 5,6-DMBA dihydrodiols, and DMBA, 2- or 3- or 4-phenol; 7-OH-methyl-12-methyl-benz(a)anthracene and 12-OH-methyl-7-methyl-benz(a)anthracene were minor metabolites. A very small amount of DMBA-3,4-dihydrodiol was detected, and polar metabolites, which did not migrate with any DMBA metabolite standards, were observed. Incubating trout hepatocytes with DMBA-3,4-dihydrodiol produced three prominent, nonpolar adducts indistinguishable from those in mouse embryo cells. However, DMBA-DNA adducts, formed in trout in vivo or in trout liver cells exposed to DMBA, were predominantly more polar than those formed in mouse embryo fibroblasts, and levels of DMBA-DNA adducts formed in trout liver cells were not significantly altered by modulating CYP1A1 activity. No significant repair of DMBA-DNA adducts was detected in cultured trout liver cells over a 48-h period, supporting previous studies indicating that fish are less efficient than mammals in repairing polyaromatic hydrocarbon DNA adducts. Compared to animals receiving DMBA alone, β-naphthoflavone pretreatment in vivo did not affect hepatic CYP1A1, DMBA-DNA adducts, nor hepatic tumor response; but did significantly reduce tumor response in two other target organs. These results collectively indicate that DMBA bioactivation to DNA-binding metabolites in trout liver cells and mouse embryo cells predominantly involve different metabolic pathways to form the DNA-binding intermediates.

Keywords: 7,12-dimethylbenz(a)anthracene; trout; liver cells; CYP1A1; DNA adducts

Journal Article.  9514 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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