Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Immunopharmacology ; 18(1): 39-55, 1989.
Article in English | MEDLINE | ID: mdl-2504682

ABSTRACT

Administration of benzene to mice causes bone marrow toxicity and elevations in prostaglandin E2 (PGE2), a negative regulator of myelopoiesis. In these experiments, benzene (400 mg/kg; 2 x/day for 2 days) administered to DBA/2 or C57Bl/6 mice decreased bone marrow cellularity and myeloid progenitor cell development (measured as colony-forming units per femur) by 40%. When inhibitors of the cyclooxygenase component of prostaglandin H synthase (PHS) (either indomethacin, 2 mg/kg; aspirin, 50 mg/kg; meclofenamate, 4 mg/kg) were coadministered with benzene, myelotoxicity and the elevation in bone marrow PGE level were prevented. Additionally, when indomethacin (1 microM) was added to cultures of bone marrow cells from benzene-treated mice, myeloid progenitor cell development was the same as the controls. The doses of indomethacin used had no affect on the hepatic conversion of benzene to its major metabolite, phenol. Using purified PHS, indomethacin (10 microM) inhibited the arachidonic acid-dependent oxidation of hydroquinone to p-benzoquinone, a putative reactive metabolite of benzene. Indomethacin (10 microM) had no effect on the H2O2-driven oxidation of hydroquinone catalysed by either PHS-peroxidase or myeloperoxidase. Coadministration of the benzene metabolites, phenol and hydroquinone, has been reported previously to reproduce the myelotoxicity of benzene. In our studies, phenol and hydroquinone (50 mg/kg each; 2 x/day for 2 days) decreased bone marrow cellularity by 40%; however, coadministration of indomethacin (2 mg/kg) or meclofenamate (4 mg/kg) with these metabolites did not prevent the decrease in bone marrow cell number. Our results implicate marrow PHS in mediating the short-term myelotoxicity of benzene.


Subject(s)
Benzene/antagonists & inhibitors , Bone Marrow Diseases/prevention & control , Cyclooxygenase Inhibitors , Dinoprostone/biosynthesis , Animals , Benzene/toxicity , Bone Marrow Diseases/chemically induced , Bone Marrow Diseases/metabolism , Bone Marrow Diseases/pathology , Cell Division/drug effects , Indomethacin/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Stem Cells/drug effects
2.
Environ Health Perspect ; 82: 57-64, 1989 Jul.
Article in English | MEDLINE | ID: mdl-2792051

ABSTRACT

Benzene affects hematopoietic progenitor cells leading to bone marrow depression and genotoxic effects such as micronucleus formation. Progenitor cell proliferation and differentiation are inhibited by prostaglandins produced by macrophages. Administration of benzene to DBA/2 or C57BL/6 mice caused a dose-dependent bone marrow depression and a significant increase in marrow prostaglandin E level and both were prevented by the coadministration of indomethacin and other inhibitors of the cyclooxygenase component of prostaglandin H synthase. Levels of benzene that decreased bone marrow cellularity also caused genotoxic effects measured as increased micronucleated polychromatic erythrocytes in peripheral blood, which was also prevented by the coadministration of indomethacin. These results suggest a possible role for prostaglandin synthase in benzene myelotoxicity; a mechanism by which this might occur is presented.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzene/toxicity , Bone Marrow Diseases/prevention & control , Animals , Arachidonic Acids/metabolism , Bone Marrow Diseases/chemically induced , Indomethacin/pharmacology , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Micronucleus Tests , Phenol , Phenols/metabolism , Prostaglandins E/metabolism
3.
Mutat Res ; 222(3): 291-8, 1989 Mar.
Article in English | MEDLINE | ID: mdl-2922013

ABSTRACT

Benzene is a myelotoxin which affects hemopoietic progenitor cells leading to bone-marrow depression as well as a genotoxin which causes chromosomal abnormalities including micronucleus formation. We have demonstrated previously that benzene administered to DBA/2 or C57B1/6 mice causes bone-marrow depression and increased prostaglandin E2 levels in bone marrow; both of these effects can be prevented by the coadministration of indomethacin, a selective inhibitor of prostaglandin synthase. We report, herein, that benzene (400-600 mg/kg body weight), under conditions where it depresses bone-marrow cellularity, also induces an increase in the frequency of micronucleus formation in polychromatic erythrocytes of C57B1/6 mice which is also prevented by the coadministration of indomethacin at levels that do not inhibit cytochrome P450 or myeloperoxidase. In Swiss Webster wild-type mice doses of benzene from 400 to 1000 mg/kg were without effect on marrow cellularity, but did induce the formation of micronucleated polychromatic erythrocytes which could be prevented by indomethacin. In contrast, DBA/2 mice, a strain highly sensitive to benzene, exhibited significant bone-marrow depression at a dose of benzene of 100 mg/kg body weight. Even at this low dose, benzene is too toxic toward developing erythrocytes to allow the evaluation of micronucleus formation. The frequency of induction of micronucleated polychromatic erythrocytes by benzene thus depends on the strain of mouse used. Furthermore, micronucleus formation appears to be an early and very sensitive indicator of benzene toxicity. A possible role for prostaglandin H synthase in the geno- and myelo-toxicity of benzene is discussed.


Subject(s)
Benzene/toxicity , Bone Marrow/drug effects , Indomethacin/therapeutic use , Micronucleus Tests , Animals , Body Weight/drug effects , Colchicine/administration & dosage , Drug Administration Schedule , Erythrocytes, Abnormal/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA
SELECTION OF CITATIONS
SEARCH DETAIL
...