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Efficient Metabolism of Benzo(a)pyrene at Nanomolar Concentrations by Intact Murine Hepatoma Cells¹

Department of Pharmacology, Stanford University School of Medicine, Stanford, California 94305

We have studied the metabolism of benzo(a)pyrene (BP) by intact mouse hepatoma cells, at nM concentrations of the carcinogen, using an assay in which we directly measure the rate of BP fluorescence disappearance. The rate of BP metabolism is half-maximal, at limiting cell dilution, when the concentration of BP is about 4 nM. This apparent K_m for BP metabolism is much lower than those reported previously for several reasons. (a) Partitioning of BP into cells markedly influences kinetic measurements, and we account for these effects. (b) Enzyme inducers can competitively inhibit BP metabolism and thus may introduce artifacts into kinetic measurements. (c) Under the conditions of this assay, phenolic BP metabolites are produced but do not accumulate, due to their further metabolism; therefore, assays of BP metabolism which measure the production of phenols, such as the commonly used aryl hydrocarbon hydroxylase assay, may markedly underestimate the rate of BP metabolism when intact cells and low substrate concentrations are used. Our results show that cells can efficiently metabolize BP when exposed to BP concentrations similar to those present in the environment.

¹ Supported by Research Grants CA 24580 and GM 17367 and Training Grant GM 07149 from the NIH and Institutional Grant IN 32S from the American Cancer Society.

² Present address: Tumor Virology Laboratory, The Salk Institute, P.O. Box 85800, San Diego, Calif. 92138.

³ Recipient of a faculty research award from the American Cancer Society.

Received 3/ 8/82. Accepted 7/26/82.