The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity

Abstract

Following po administration of a nephrotoxic dose (200 mg/kg) of hexachloro-1:3-butadiene (HCBD) to male rats, the principal route of excretion was biliary, 17–20% of the dose being eliminated on each of the first 2 days. Fecal excretion over this period was less than 5% of the dose per day, suggesting enterohepatic recirculation of biliary metabolites. Urinary excretion was small, not exceeding 3.5% of the dose during any 24-hr period. The major biliary metabolite was a direct conjugate between glutathione and HCBD itself. The cysteinylglycine conjugate of HCBD has also been found in bile. Evidence was obtained to show that biliary metabolites of HCBD are reabsorbed and excreted via the kidneys. The glutathione conjugate, its mercapturic acid derivative, and bile containing HCBD metabolites were all nephrotoxic when dosed orally to rats. In common with HCBD, these metabolites caused localized damage to the kidney with minimal effects in the liver. Rats fitted with a biliary cannula were completely protected from kidney damage when dosed with HCBD, demonstrating that hepatic metabolites were solely responsible for the nephrotoxicity of this compound. It is proposed that the hepatic glutathione conjugate of HCBD was degraded to its equivalent cysteine conjugate which was cleaved by the renal cytosolic enzyme β-lyase to give a toxic thiol which caused localized kidney damage. A urinary sulphenic acid metabolite of HCBD has been identified which is consistent with this hypothesis. The mode of activation of HCBD conjugates in the kidney is believed to be analogous to that proposed for S-(1,2-dichlorovinyl)- l-cysteine.