An interaction of benzene metabolites reproduces the myelotoxicity observed with benzene exposure.
Benzene-induced myelotoxicity can be reproduced by the coadministration of two principal metabolites, phenol and hydroquinone. Coadministration of phenol (75 mg/kg) and hydroquinone (25-75 mg/kg) twice daily to B6C3F1 mice for 12 days resulted in a significant loss in bone marrow cellularity in a manner exhibiting a dose-response. One explanation for this potentiation is that phenol stimulates the peroxidase-dependent metabolism of hydroquinone. Addition of phenol to incubations containing horseradish peroxidase, H2O2, and hydroquinone resulted in a stimulation of both hydroquinone removal and benzoquinone formation. Stimulation occurred with phenol as low as 100 microM and with very low concentrations of horseradish peroxidase. When boiled rat liver protein was added to identical incubations containing [14C]hydroquinone, the level of radioactivity recovered as protein bound increased by 37% when phenol was added. Similar results were observed when [14C]hydroquinone was incubated in the presence of activated human leukocytes. Hydroquinone binding was increased by approximately 70% in the presence of phenol. Phenol-induced stimulation of hydroquinone metabolism and benzoquinone formation represents a likely explanation for the bone marrow suppression associated with benzene toxicity.
Eastmond
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Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley 94720.
Smith
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D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones; D001853:Bone Marrow / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D009195:Peroxidase / Q000378:metabolism*; D019800:Phenol; D010636:Phenols / Q000378:metabolism / Q000633:toxicity*; D011809:Quinones / Q000378:metabolism
D016227:Benzoquinones; D006873:Hydroquinones; D010636:Phenols; D011809:Quinones; D019800:Phenol; C004532:quinone; D006735:Horseradish Peroxidase; D009195:Peroxidase; D001554:Benzene