Chemical modulation of 1,2-dibromo-3-chloropropane toxicity.
Single subcutaneous injections of 1,2-dibromo-3-chloropropane (DBCP) produced dose-dependent injury to the kidney, testis, epididymis and liver of male, Fischer 344 rats. Pretreatment with the enzyme inducer phenobarbital reduced the nephrotoxic potency of DBCP. Serum creatinine and urea nitrogen concentrations were lower, and renal proximal tubular necrosis was less severe in phenobarbital pretreated than in non-pretreated rats subsequently injected with various amounts of DBCP. 3-Methylcholanthrene (3-MC) or cobaltous chloride (CoCl2) pretreatments enhanced the dose-dependent necrogenic effects of DBCP on the kidney and, in general, potentiated the DBCP-induced elevations of serum creatinine and urea nitrogen concentrations. Pre- and post-treatment with the enzyme inhibitor piperonyl butoxide had no discernable effect on the nephrotoxic potency of DBCP. The hepatotoxic potency of DBCP, as measured by elevations in the serum activities of glutamic pyruvic transaminase (GPT) and sorbitol dehydrogenase (SDH), and by histological analysis of the severity of centro lobular necrosis, was prevented or quantitatively reduced by phenobarbital pretreatment. 3-MC, CoCl2 or piperonyl butoxide pretreatments had no consistent effect on DBCP hepatotoxicity. The dose-dependent seminiferous tubular atrophy induced in rats by DBCP was enhanced by CoCl2 and reduced by phenobarbital. Cobalt chloride pretreatment also enhanced the DBCP-induced degeneration of the epithelium of the caput (head) epididymis, while phenobarbital blocked or reduced this effect. Neither 3-MC nor piperonyl butoxide consistently altered the gonadotoxic potency of DBCP. Cobalt chloride also enhanced, while phenobarbital reduced, the acute lethal potency of DBCP. Single-treatment, subcutaneous LD50 values for DBCP were 102 mg/kg in non-pretreated and 128 mg/kg in phenobarbital pretreated rats. The potency ratio (0.796; confidence interval, 0.728-0.871) was statistically significant (P less than 0.05). The modulating effects of CoCl2 and phenobarbital could not be ascribed simply to changes in tissue concentrations of the protective conjugation substrate glutathione, since CoCl2 increased and phenobarbital did not alter renal and hepatic non-protein sulfhydryl concentrations. These data indicate a complex role of metabolism in determining dose-dependent toxic response to DBCP administration.
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D003035:Cobalt / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced; D007928:Lethal Dose 50; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013737:Testis / Q000187:drug effects
D013438:Sulfhydryl Compounds; D003035:Cobalt; D008748:Methylcholanthrene; C007318:1,2-dibromo-3-chloropropane; C018021:cobaltous chloride; D010882:Piperonyl Butoxide; D011407:Propane; D010634:Phenobarbital