Comparison of the metabolism of benzo[a]pyrene and its activation to biologically active metabolites by low-passage hamster and rat embryo cells

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Abstract
The activity of benzo[a]pyrene (BP) in cell transformation and cell-mediated mutation assays in which the hydrocarbon was activated by Wistar-Lewis rat embryo (RE) or hamster embryo (HE) cells was compared, and the metabolism of BP was analyzed under the culture conditions of the assays. In the transformation assay, BP (0.1 μg/ml) decreased the cloning efficiency of HE target cells 74% with RE feeder cells, whereas with HE cells as feeders, BP (10 μg/ml) produced little toxicity. In the cell-mediated mutation assay, BP (0.5 μg/ml) reduced the cloning efficiency of V79 target cells 40% with either RE or HE cells as activators. Under the high-cell density conditions of the mutation assay, the major [ 3 H]BP metabolites formed in both cell types were dihydrodiols and phenol-glucuronides. RE cells formed similar amounts of BP-9, 10-diol and BP-7, 8-diol; HE cells formed four times as much BP-9, 10-diol as BP-7, 8-diol. The ratio of the glucuronide conjugates of 3-hydroxy-BP to 9-hydroxy-BP was 2:1 in RE cells and 1:2 in HE cells. Under the low-cell density conditions of the transformation assay, the [ 3 H]BP metabolites released into the medium were dihydrodiols, phenol-glucuronides and substantial amounts of free phenols, mainly 9-hydroxy-BP in HE cells and both 9-hydroxy-BP and 3-hydroxy-BP in RE cells. Differences in the ratios of specific free phenols and of the two dihydrodiols which are produced and released into the medium by the two cell types may explain, in part, the differences in BP-induccd toxicity under conditions of the transformation assay. In fact, under such conditions, 3-hydroxy-BP (1 μg/ml) reduced the cloning efficiency of HE target cells 50% with both RE and HE feeder cells whereas 9-hydroxy-BP had no effect; BP-7,8-diol (0.1μg/ml) reduced the cloning efficiency 60% with RE feeder cells but had little effect with HE feeder cells. These experiments indicate that differences in carcinogen metabolism at different cell densities should be considered in designing and interpreting short-term screening assays.

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