TY - JOUR
T1 - Neutrophil-derived oxidants as mediators of chemical activation in bone marrow
AU - Twerdok, Lorraine E.
AU - Trush, Michael A.
N1 - Funding Information:
We gratefully acknowledge the financial support for this research by the American Cancer Society #1N-11X and SIG-3, and the National Institutes of Health ES 07141 and ES 03760.
PY - 1988
Y1 - 1988
N2 - 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.
AB - 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.
KW - Bone marrow
KW - Polycyclic aromatic hydrocarbons
KW - Reactive oxygen
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U2 - 10.1016/0009-2797(88)90111-1
DO - 10.1016/0009-2797(88)90111-1
M3 - Article
C2 - 2837335
AN - SCOPUS:0023938109
SN - 0009-2797
VL - 65
SP - 261
EP - 273
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 3
ER -