Neutrophil-derived oxidants have been implicated in both the damage to biomolecules and the metabolic activation of xenobiotics. Bone marrow, a relatively neutrophil-rich tissue with low cytochrome P450 activity, is subject to toxicity from orally administered benzo[a]pyrene (BP) in mice with noninducible P450 monooxygenase systems. Thus, we have compared the oxidant generation and chemical activation by neutrophilic cells isolated from femurs of male DBA 2 and C57Bl 6 mice, strains that are susceptible and nonsusceptible, respectively, to bone marrow toxicity from BP. Oxidant generation of neutrophilic preparations was assayed by superoxide anion generation and oxidant-dependent chemiluminescence (CL) from luminol or lucigenin. In all assays, cells from DBA 2 mice demonstrated increased oxidant generation. CL from BP-7,8-dihydrodiol (BP-diol) has previously been shown to correlate with its ability to elicit genotoxic effects. A twofold enhancement of oxidant-dependent CL from BP-diol was observed with TPA-stimulated neutrophilic cells from DBA 2 mice as compared to cells from C57Bl 6 mice. DBA 2-derived bone marrow cells also activated more BP-diol to a DNA covalent binding species than did bone marrow cells derived from the less BP-sensitive C57Bl 6 mouse. Tetraol analysis of BP-diol metabolism by activated bone marrow cells confirmed this greater bioactivation of the diol by DBA 2-derived cells. These results suggest that the increased risk of DBA 2 mice for BP-induced bone marrow toxicity may be related to their greater ability to bioactivate xenobiotics through oxidant-dependent mechanisms.
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