In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene

Hexachlorobutadiene (HCBD), a renal toxin and carcinogen, is thought to require bioactivation to exert toxicity. The chemically synthesized cysteine conjugate of structurally simitar haiogenated hydrocarbons, trichloroethylene, chlorotrifluoro- ethylene, and chlorodifluoroethylene, have been shown to be nephrotoxic. Hence the cysteine conjugate of HCBD, S-pentachlorobuta-l,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 1O^-3 M PCBC completely inhibited active transport, in addition, in vivo exposure of Swiss-Webster male mice caused dose-dependent damage in the pars recta region of the proximal tubules (5-25 mgjkg ip). Genotoxicity in renal tissue was studied by using alkaline elution to detect DNA singlestrand breaks and total cross-links. No DNA single-strand breaks were observed in isolated rabbit renal tubules after exposure to 10^-3 to 10^-5 M PCBC. However, at I0^-3 M PCBC there was some evidence of DNA cross-links. Therefore if cysteine conjugates of HCBD are formed in vivo, they could account for the toxicity observed with exposure to HCBD.