Nephrotoxicity of hexachloro-1,3-butadiene in the mouse: the effect of age, sex, strain, monooxygenase modifiers, and the role of glutathione.
Administration of a single ip dose of hexachloro-1,3-butadiene (HCBD) to adult male or female Alderley Park mice at 96 mumol/kg or above produced renal tubular necrosis of the pars convoluta and pars recta of the proximal tubule by 24 hr. Renal damage was also observed biochemically by the reduced accumulation of the organic anion (p-aminohippurate) and organic cation (tetraethylammonium) by renal slices and by an elevated plasma urea. The toxicity of HCBD to adult Alderley Park mice was similar for males and females. Young male mice (21 and 28 days old) were slightly more susceptible to HCBD-induced nephrotoxicity than adult (7-week-old) males. A strain difference in susceptibility to HCBD-induced renal damage was observed, the BALB/c strain being slightly more sensitive than C57BL/10J, C3H, DBA/2J, and Alderley Park strains. This strain difference was reflected in the lethality of HCBD to mice. Prior administration of the monooxygenase inducers, phenobarbitone or beta-naphthoflavone, or of the monooxygenase inhibitor, piperonyl butoxide, did not alter the extent of renal damage produced by HCBD in male Alderley Park mice. However, HCBD produced a marked decrease in kidney but not liver nonprotein sulfydryl content in this strain of mouse, suggesting the formation of glutathione conjugates in the kidney. Administration of the glutathione or N-acetylcysteine conjugates of HCBD produced a marked renal tubular necrosis similar to that seen with HCBD. It is suggested that the mechanism of HCBD-induced nephrotoxicity in the mouse involves nonoxidative metabolism of HCBD in the kidney and that the cysteine conjugates formed are further metabolized to a nephrotoxic agent.
D000111:Acetylcysteine / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000139:chemically induced*; D000375:Aging; D000818:Animals; D002070:Butadienes / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000473:pathology; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012737:Sex Factors; D013045:Species Specificity; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D014508:Urea / Q000097:blood; D010130:p-Aminohippuric Acid / Q000378:metabolism
D002070:Butadienes; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D014508:Urea; C001335:hexachlorobutadiene; D005978:Glutathione; D000111:Acetylcysteine; D010130:p-Aminohippuric Acid