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Morphological Transformation and DNA Adduct Formation by Benz[j]aceanthrylene and Its Metabolites in C3H10TCL8 Cells: Evidence for Both Cyclopenta-Ring and Bay-Region Metabolic Activation Pathways¹

Carcinogenesis and Metabolism Branch, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711 [S. N., J. R.]; Environmental Health Research and Testing, Research Triangle Park, North Carolina 27709 [J. L., S. C., G. N.]; and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514 [R. S., A. G.]

Benz[j]aceanthrylene (B[j]A), a cyclopenta-fused polycyclic aromatic hydrocarbon related to 3-methylcholanthrene, has been studied to identify the major routes of metabolic activation in transformable C3H10TCL8 (C3H10T) mouse embryo fibroblasts in culture. Previous studies have reported that the major (55% of total) B[j]A metabolite formed by C3H10T cells was (±)-trans-9,10-dihydro-9,10-dihydroxy-B[j]A (B[j]A-9,10-diol), the dihydrodiol in the bay-region ring, with moderate amounts (14% of total) of (±)-trans-1,2-dihydro-1,2-dihydroxy-B[j]A (B[j]A-1,2-diol), the cyclopenta-ring dihydrodiol. The morphological transforming activities of three potential intermediates formed by metabolism of B[j]A by C3H10T cells, (±)-anti-trans-9,10-dihydro-9,10-dihydroxy-B[j]A-7,8-oxide (B[j]A-diol-epoxide), B[j]A-9,10-oxide, and B[j]A-1,2-oxide as well as the two B[j]A-dihydrodiols were examined. B[j]A, B[j]A-diol-epoxide, B[j]A-1,2-oxide, and B[j]A-9,10-diol were found to have moderate to strong activities with B[j]A-diol-epoxide the most active compared to B[j]A, while B[j]A-1,2-diol was inactive. B[j]A-9,10-oxide was found to be a weak transforming agent. At 0.5 µg/ml, the following percentage of dishes with type II or III foci were observed: B[j]A, 59%; B[j]A-diol-epoxide, 75%; B[j]A-1,2-oxide, 25%; and B[j]A-9,10-diol, 17%. DNA adducts of B[j]A, B[j]A-9,10-diol, B[j]A-diol-epoxide, B[j]A-9,10-oxide, and B[j]A-1,2-oxide in C3H10T cells were isolated, separated, identified, and quantitated using the ³²P-postlabeling method. B[j]A forms two major groups of adducts: one group of adducts is the result of the interaction of B[j]A-1,2-oxide with 2'-deoxyguanosine and 2'-deoxyadenosine; the second group of adducts is a result of the interaction of B[j]A-diol-epoxide with 2'-deoxyguanosine and 2'-deoxyadenosine.

Qualitative and quantitative analysis of the postlabeling data suggests that B[j]A is metabolically activated by two distinct routes, the bayregion diol-epoxide route and the cyclopenta-ring oxide route, the former being the most significant.

¹ This work was supported in part by the United States Environmental Protection Agency, Grant CR-811817, and Contract 68-02-4031, and USPHS Grant CA47964. The research described in this article has been reviewed by the Health Effects Research Laboratory, United States Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

² To whom requests for reprints should be addressed, at Carcinogenesis and Metabolism Branch, MD-68, Genetic Toxicology Division, United States Environmental Protection Agency, Research Triangle Park, NC 27711.

Received 2/14/91. Accepted 9/ 9/91.

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