The role of ortho-bromophenol in the nephrotoxicity of bromobenzene in rats.
ortho-Bromophenol (1.92 mmol/kg, ip) caused a 50% decrease in renal glutathione levels within 90 min. In contrast, hepatic glutathione levels remained 80% of control values 5 hr after ortho-bromophenol administration. Renal glutathione was far more susceptible to the initial rapid depleting effects of ortho-bromophenol than was hepatic glutathione, the dose-response curve for hepatic glutathione depletion being shifted to the right. ortho-Bromophenol at doses greater than 1.6 mmol/kg caused severe renal necrosis in noninduced rats, with consequent elevations in BUN levels. This dose was one-fifth as large as that required by bromobenzene to produce a similar necrosis in phenobarbital-treated rats (W. D. Reid, Exp. Mol. Pathol., 19, 197-214, 1973). Phenobarbital pretreatment and depletion of tissue glutathione with diethyl maleate caused significant increases in BUN levels over controls. Pretreatment with piperonyl butoxide decreased the incidence of elevated BUN levels following ortho-bromophenol administration. While liver microsomes converted ortho-bromophenol to covalently bound material, kidney microsomes did not. However, in vivo, ortho-bromophenol covalently bound to kidney protein of control rats four times greater than to liver protein. Phenobarbital pretreatment increased the in vivo covalent binding to kidney protein but not to liver protein. The degree of covalent binding to kidney protein correlated with BUN levels (r = 0.91, p less than 0.001). The nature of the nephrotoxic metabolite of ortho-bromophenol is not known, but an intermediate may be generated in the liver and transported to the kidney. These findings suggest that ortho-bromophenol may play a role in the nephrotoxicity observed following bromobenzene administration.
D000818:Animals; D001806:Blood Urea Nitrogen; D001969:Bromobenzenes / Q000633:toxicity*; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism*; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000378:metabolism / Q000633:toxicity*; D010882:Piperonyl Butoxide / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001969:Bromobenzenes; D008298:Maleates; D010636:Phenols; C032038:2-bromophenol; C014476:diethyl maleate; D005978:Glutathione; D010882:Piperonyl Butoxide