In vivoandin vitronephrotoxicity of the cysteine conjugate of hexachlorobutadiene

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Abstract
Hexachlorobutadiene (HCBD), a renal toxin and carcinogen, is thought to require bioactivation to exert toxicity. The chemically synthesized cysteine conjugate of structurally similar halogenated hydrocarbons, trichloroethylene, chlorotrifluoroethylene and chlorodifluororethylene, have been shown to be nephrotoxic. The cysteine conjugate of HCBD, S-phentachlorobuta-1,3-dienyl cysteine (PCBC), was assessed for potential nephrotoxicity. Active acid and base transport in isolated rabbit renal tubules was used to screen nephrotoxicity. A dose-dependent decrease in acid and base transport was observed after incubation with PCBC. At 10-5 M PCBC transport was similar to that in controls, while at 10-3 M PCBC completely inhibited active transport. In vivo exposure of Swiss-Webster male mice caused dose-dependent damage in the pars recta region of the proximal tubules (5-25 mg/kg i.p.). Genotoxicity in renal tissue was studied by using alkaline elution to detect DNA single-strand breaks and total cross-links. No DNA single-strand breaks were observed in isolated rabbit renal tubules after exposure to 10-3-10-5 M PCBC. At 10-3 M PCBC there was some evidence of DNA cross-links. If cysteine conjugates of HCBD were formed in vivo, they could have accounted for the toxicity observed with exposure to HCBD.