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© 1991 Oxford University Press

research-article

Metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol in human mammary epithelial cells: feedback inhibition by 7-hydroxybenzo[a]pyrene

Allan N. Tischler, Gerri A. Levine and Jack C. Bartley

Division of Cell and Molecular Biology, Lawerence Berkeley Laboratory Berkeley, CA 94720, USA

The metabolism of benzo[a]pyrene (B[a]P) and (–)-transbenzo[a]pyrene-7,8-dihydrodiol (B[a]P-diol) was compared in human mammary epithelial cells (HMEC) grown in serum-free medium, MCDB-170. Conversion of B[a]P-diol to the carcinogen (+)-benzo[a]pyrene-7,8-dihydroxy-9,l0-epoxide (BPDE), as measured by of their tetrol hydrolysis products, occurred much more efficiently in cultures incubated with [3H]B[a]P-diol than in cultures incubated with [3H]B[a]P. In cultures pretreated with unlabeled B[a]P (24 h, 400 nM), the conversion of [3H]B[a]P-diol to [3H]tetraols is inhibited 49%, while the conversion of [3H]B[a]P to [3]B[a]P-diol is not affected. These observations led to the identification of a major B[a]Pderived metabolite as 7-hydroxybenzo[a]pyrene (B[a]P-7-ol), which was found to be an extremely potent and selective inhibitor of tbe conversion of B[a]P-diol to BPDE, with a K1 estimated at 3–12 nM. Thus B[a]P activation in HMEC appears to be significantly limited by a feedback inhibition pathway induced by B[a]P-7-ol. The potency and selectivity of the B[a]P-7-ol-induced inhibition suggests that the diol to diolepoxide conversion is affected by a selective oxygenase in HMEC, rather than a non-enzymatic, peroxy radicalinduced mechanism. B[a]P-7-ol should prove to be a valuable tool in the study of B[a]P carcinogenesis.


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