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Benzo(e)pyrene-induced Alterations in the Metabolic Activation of Benzo(a)pyrene and 7,12-Dimethylbenz(a)anthracene by Hamster Embryo Cells¹

Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907 [W. M. B., C. P. S.], and The Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104 [L. D.]

Benzo(e)pyrene (BeP) is a cocarcinogen with benzo(a)pyrene (BaP) and an anticarcinogen with 7,12-dimethylbenz(a)anthracene (DMBA) in mouse skin initiation-promotion assays (Slaga, T. J., Jecker, L., Bracken, W. M. and Weeks C. E. Cancer Lett. 7: 51–59, 1979). We have investigated the effects of BeP on the metabolic activation of BaP and DMBA in early-passage cultures of Syrian hamster embryo cells. BeP had no effect on BaP-induced mutation frequencies in hamster embryo cell-mediated assays with V79 target cells. However, it inhibited the DMBA-induced mutagenesis by as much as 10-fold at the highest dose tested.

Low doses of BeP did not affect the total amount of BaP metabolized, but the proportion of water-soluble metabolites was reduced, and the proportions of trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene and trans-9,10-dihydro-9,10-dihydroxybenzo-(a)pyrene were increased. Higher doses did decrease BaP metabolism and caused similar alterations in the metabolite profile. In cultures treated with trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, BeP greatly reduced the oxidative metabolism of this diol. BeP inhibited DMBA metabolism at all doses tested; the proportion of water-soluble metabolites formed was decreased, and the proportions of trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz(a)anthracene and trans-3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz(a)anthracene were increased.

The results demonstrate that BeP is an effective inhibitor of the secondary oxidation of carcinogenic hydrocarbon diols required to convert diols which are proximate carcinogens to ultimate carcinogens such as diol-epoxides. The balance between (a) limited inhibition with consequent increase in total exposure to the ultimate carcinogenic form and (b) sufficient inhibition to reduce exposure to the ultimate carcinogenic form may determine whether BeP acts as a co- or anticarcinogen with a particular carcinogenic hydrocarbon.

¹ Supported in part by Grants CA28825 and CA10815, from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 10/ 6/83. Accepted 1/ 4/84.