Nephrotoxicity of phenolic bromobenzene metabolites in the mouse.
Bromobenzene, at doses greater than 5.7 mmol/kg, produced renal proximal tubular necrosis and renal functional changes in mice. p-Bromophenol and o-bromophenol were the major urinary phenolic bromobenzene metabolites although m-bromophenol and 4-bromocatechol were also excreted in detectable quantities. With the exception of o-bromophenol, urinary metabolites were excreted primarily as conjugates. 4-Bromocatechol and the 3 bromophenol isomers were nephrotoxicants (measured as increased blood urea nitrogen and decreased accumulation of organic anions by renal cortical slices) but not hepatotoxicants (measured as serum glutamic pyruvate transaminase) in vivo at 0.56 mmol/kg (i.v.). Preincubation of renal cortical slices with each of these bromobenzene metabolites for 90 min resulted in dose-dependent decreases in the accumulation of p-aminohippurate and tetraethylammonium. At 10 mumol/preincubation (2.4 mM), organic ion accumulation was decreased maximally by all bromobenzene metabolites examined while equimolar amounts of bromobenzene were without effect. 4-Bromocatechol was the most potent nephrotoxicant in vitro. Administration of 0.53-2.12 mmol/kg (i.v.) 4-bromocatechol to mice resulted in a dose-dependent decrease in renal function while hepatic function was altered only slightly at the higher doses. The renal cortical necrosis produced by in vivo administration of 4-bromocatechol could not be distinguished histologically from that induced by bromobenzene. These results demonstrate that 4-bromocatechol and the 3 bromophenol isomers are nephrotoxicants that can be generated from bromobenzene in mice.
D000818:Animals; D001806:Blood Urea Nitrogen; D001969:Bromobenzenes / Q000378:metabolism* / Q000633:toxicity; D002396:Catechols / Q000633:toxicity / Q000652:urine; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D010636:Phenols / Q000633:toxicity / Q000652:urine; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D001969:Bromobenzenes; D002396:Catechols; D010636:Phenols; D013757:Tetraethylammonium Compounds; C040660:4-bromocatechol; D019789:Tetraethylammonium; C032038:2-bromophenol; C032036:bromobenzene; C032037:4-bromophenol; C040659:3-bromophenol; D010130:p-Aminohippuric Acid