title: Neutrophil-derived oxidants as mediators of chemical activation in bone marrow.
abstract: Neutrophil-derived oxidants have been implicated in both damage to biomolecules and the metabolic activation of xenobiotics. Since the bone marrow is a relatively neutrophil-rich tissue which is subject to xenobiotic toxicity, we have characterized the oxidant generating capability of neutrophilic cells isolated from femurs of male C57BL/6J mice. Addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to neutrophil preparations (70 +/- 5% ring neutrophils and metamyelocytes) elicited superoxide anion generation, as indicated by superoxide dismutase (SOD)-inhibitable acetylated cytochrome c reduction, and oxidant-dependent chemiluminescence (CL) from luminol or lucigenin. The interaction of benzo[a]pyrene-7,8-dihydrodiol (BP-diol), a proximate carcinogenic metabolite of benzo[a]pyrene (BP), with TPA-stimulated bone marrow neutrophils resulted in azide-inhibitable CL (90%) indicative of its myeloperoxidase-dependent oxidation to an excited-state intermediate. Covalent binding of [3H]BP-diol to exogenous DNA was similarly increased 3-fold in the presence of TPA-stimulated bone marrow neutrophils. Recently, our laboratory has shown that in addition to CL, TPA-stimulated human polymorphonuclear leukocytes can activate BP-diol to an intermediate which covalently binds to DNA and elicits mutagenicity in Salmonella typhimurium TA100. These observations combined with our current results suggest a possible role for neutrophil-derived oxidants in the mechanisms of chemically-induced bone marrow toxicity.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205.
authors.forename: L E
authors.initials: LE
authors.lastname: Twerdok
authors.forename: M A
authors.initials: MA
authors.lastname: Trush
mesh_terms: D000166:Acridines; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001711:Biotransformation; D001854:Bone Marrow Cells; D004247:DNA / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism; D008163:Luminescent Measurements; D008165:Luminol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000166:Acridines; D001386:Azides; D004101:Dihydroxydihydrobenzopyrenes; D013481:Superoxides; C017228:benzo(a)pyrene 7,8-dihydrodiol; C033472:10,10'-dimethyl-9,9'-biacridinium; D008165:Luminol; D004247:DNA; D009195:Peroxidase; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen