The role of 4-bromophenol and 4-bromocatechol in bromobenzene covalent binding and toxicity in isolated rat hepatocytes.
4-Bromophenol and 4-bromocatechol are formed as metabolites of bromobenzene in vivo and in isolated rat hepatocytes. Both of these metabolites may potentially contribute to the hepatotoxicity of bromobenzene. Bromobenzene metabolism in hepatocytes isolated from phenobarbital-treated rats forms 0.12 to 0.17 mM 4-bromophenol and 4-bromocatechol in 2 hr, with 1 to 3 mM bromobenzene. The role of activated metabolites derived from 4-bromophenol and 4-bromocatechol in bromobenzene covalent binding and toxicity was investigated with isolated hepatocytes in suspension. The covalent binding of the phenol and the catechol was increased four- to eightfold by the addition of unlabeled bromobenzene. Two-hour incubations of 0.25 mM 14C-labeled 4-bromophenol or 4-bromocatechol with hepatocytes isolated from phenobarbital-treated rats resulted, under these conditions, in no significant toxicity, and approximately 4 and 25%, respectively, of the covalent binding associated with bromobenzene itself. Two- and six-hour incubations with higher 4-bromophenol and 4-bromocatechol concentrations demonstrated that 1 to 3 mM substrate concentrations were required for cytotoxicity. These results show that metabolically produced 4-bromophenol and 4-bromocatechol do not play significant roles in the production of bromobenzene cytotoxicity in isolated hepatocytes, and that they contribute only modestly to bromobenzene covalent binding.
D000818:Animals; D001969:Bromobenzenes / Q000378:metabolism* / Q000633:toxicity; D002250:Carbon Radioisotopes; D002396:Catechols / Q000633:toxicity*; D003603:Cytotoxins / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007424:Intracellular Fluid / Q000032:analysis; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D001969:Bromobenzenes; D002250:Carbon Radioisotopes; D002396:Catechols; D003603:Cytotoxins; D010636:Phenols; C040660:4-bromocatechol; C032036:bromobenzene; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; C032037:4-bromophenol; D010634:Phenobarbital