Formation of nontoxic reactive metabolites of p-bromophenol. Identification of a new glutathione conjugate.
A microsomal metabolite of p-bromophenol was isolated and identified as 6-(glutathion-S-yl)-4-bromocatechol. p-Bromophenol is metabolized in rat liver microsomes in part to 4-bromocatechol. The catechol undergoes autooxidation to the corresponding quinone or semiquinone, which can either covalently bind to microsomal protein or, in the presence of glutathione, form a glutathione conjugate. Superoxide dismutase inhibited these reactions by preventing the superoxide anion-mediated oxidation of 4-bromocatechol. Thus, in the presence of glutathione, superoxide dismutase caused a decrease in conjugate formation with a corresponding increase in 4-bromocatechol levels. Conditions which increased the in vitro covalent binding of p-bromophenol (namely, phenobarbital treatment and the absence of glutathione) did not cause toxicity in vivo. Thus, chemically reactive metabolite(s) of p-bromophenol do not play a role in bromobenzene-mediated hepatotoxicity.
D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity; D002396:Catechols / Q000378:metabolism / Q000633:toxicity; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism
D001969:Bromobenzenes; D002396:Catechols; D010636:Phenols; C042789:6-(glutathion-S-yl)-4-bromocatechol; C032036:bromobenzene; D013482:Superoxide Dismutase; D005978:Glutathione; C032037:4-bromophenol; D010634:Phenobarbital