s-pentachlorobuta-1-3-dien-yl-cysteine and Necrosis

The formation of cysteine S-conjugates is thought to play an important role in the nephrotoxicity of haloalkenes such as trichloroethene, tetrachloroethene and hexachlorobutadiene. Glutathione S-conjugates formed from these haloalkenes in the liver are processed to the corresponding cysteine S-conjugates, which may be N-acetylated to mercapturic acids and may be accumulated in the kidney. Haloalkene-derived cysteine S-conjugates are also substrates for cysteine conjugate beta-lyases and reactive intermediates are formed in this reaction. The equilibrium between cysteine S-conjugate and mercapturic acid thus influences the extent of beta-lyase dependent bioactivation and subsequently the nephrotoxicity of S-conjugates. In this study, we compared the rates of N-acetylation in vitro and the biotransformation, excretion and nephrotoxicity of S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCVC), S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCVC), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) and S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBC) in rats after i.v. injection (40 micromoles/kg). Marked differences in the extent of enzymatic N-acetylation were observed; N-acetylation was most efficient with 2,2-DCVC and least efficient with 1,2-DCVC. In urine, within 48 h, most of the given 2,2-DCVC (77% of the recovered dose) and 1,2-DCVC (92%) were recovered as the corresponding mercapturic acids. In contrast, a higher percentage of cysteine S-conjugate and less of the mercapturic acid were recovered in urine after administration of PCBC and TCVC (50 and 23% of dose as mercapturic acid), respectively. Histopathological examination of the kidneys and urine clinical chemistry showed marked differences in the extent of renal damage. Necroses of the proximal tubules were found after TCVC, PCBC and 1,2-DCVC administration in male, but not in female rats. These differences in nephrotoxicity do not correlate with the balance of acetylation/deacetylation. The higher toxicity observed in male rats may indicate the involvement of other parameters such as uptake mechanisms.

Topics: Acetylation; Acetylcysteine; Animals; Biotransformation; Butadienes; Cysteine; Female; gamma-Glutamyltransferase; Kidney; Liver; Male; Necrosis; Rats; Rats, Wistar; Sex Factors

The nephrotoxicity of hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and its N-acetyl cysteine conjugate (HCBD-NAC) were compared in male and female Alderley Park rats. Rats, six to eight weeks of age, were given a single intra-peritoneal injection of HCBD or its conjugates and killed 24 hours later. Nephrotoxicity was assessed by histological examination and plasma urea. All three glutathione-derived conjugates produced an elevation of plasma urea and proximal renal tubular necrosis with a similar localization in the pars recta as seen with HCBD. All the conjugates were more nephrotoxic than HCBD itself. HCBD was about four times more toxic to female rats than males. This sex difference was also shown by all the HCBD metabolites.

Topics: Acetylcysteine; Animals; Butadienes; Cysteine; Female; Glutathione; Kidney Diseases; Kidney Medulla; Kidney Tubules, Proximal; Male; Necrosis; Rats; Sex Factors; Urea