Comparison of oxidant-generation and BP-diol activation by bone marrow cells from C57Bl/6 and DBA/2 mice: implications for risk of bone marrow toxicity induced by polycyclic hydrocarbons.
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.
Twerdok
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LE
Johns Hopkins University School of Hygiene and Public Health, Department of Environmental Health Sciences, Baltimore, Maryland 21205.
Mosebrook
D R
DR
Trush
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MA
D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells; D004101:Dihydroxydihydrobenzopyrenes / Q000493:pharmacokinetics*; D008163:Luminescent Measurements; D008165:Luminol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011083:Polycyclic Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D013481:Superoxides / Q000378:metabolism*
D000166:Acridines; D004101:Dihydroxydihydrobenzopyrenes; D011083:Polycyclic Compounds; D013481:Superoxides; C017228:benzo(a)pyrene 7,8-dihydrodiol; C033472:10,10'-dimethyl-9,9'-biacridinium; D008165:Luminol; D009195:Peroxidase