Critical issues in benzene toxicity and metabolism: the effect of interactions with other organic chemicals on risk assessment.
Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene are well documented and include aplastic anemia and pancytopenia. Some individuals exposed repeatedly to cytotoxic concentrations of benzene develop acute myeloblastic anemia. It has been hypothesized that metabolism of benzene is required for its toxicity, although administration of no single benzene metabolite duplicates the toxicity of benzene. Several investigators have demonstrated that a combination of metabolites (hydroquinone and phenol, for example) is necessary to duplicate the hematotoxic effect of benzene. Enzymes implicated in the metabolic activation of benzene and its metabolites include the cytochrome P450 monooxygenases and myeloperoxidase. Since benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. Other organic molecules that are substrates for cytochrome P450 can inhibit the metabolism of benzene. For example, toluene has been shown to inhibit the oxidation of benzene in a noncompetitive manner. Enzyme inducers, such as ethanol, can alter the target tissue dosimetry of benzene metabolites by inducing enzymes responsible for oxidation reactions involved in benzene metabolism. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes, such as enzymatic oxidation, and deactivation processes, like conjugation and excretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Medinsky
M A
MA
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Schlosser
P M
PM
Bond
J A
JA
D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects* / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D019800:Phenol; D010636:Phenols / Q000378:metabolism; D018570:Risk Assessment; D013997:Time Factors; D014050:Toluene / Q000494:pharmacology*
D006873:Hydroquinones; D010636:Phenols; D019800:Phenol; D014050:Toluene; D000431:Ethanol; D001554:Benzene; C031927:hydroquinone