| Popis: |
Excretion, covalent binding and metabolism of hexachloro-1,3-butadiene (HCBD), a nephrotoxic and nephrocarcinogenic compound, have been studied in female rats. Seventy-two hours after administration of a single oral dose of 1 mg/kg [14C]HCBD, 5.3% of the dose were exhaled as unchanged HCBD and 76.3% were metabolized and excreted in urine and feces or exhaled as 14CO2. After a 50 mg/kg dose of [14C]HCBD, the amount of exhaled parent compound was nearly unchanged at 5.4%. At the higher dose the gastro-intestinal absorption of HCBD appeared to be saturated with the result that unchanged HCBD constituted the major portion of the 69% radioactivity eliminated. Covalent binding to proteins in kidney and liver agreed well with the organ-specific toxicity of HCBD: binding was higher in the kidney, independent of the dose. It increased significantly when the rats were pretreated with phenobarbital, an inducer of monooxygenases; it decreased when the inhibitor piperonyl butoxide was given. Urinary radioactivity in 24 hr urine was separated by column chromatography into four fractions. High performance liquid chromatography, radio gas chromatography and gas chromatography/mass spectrometry were used for further separation and identification. Two major metabolites were identified as pentachlorobutadiene methylthio ether and pentachlorobutadiene carboxymethylthio ether. Their formation is plausibly explained via glutathione conjugation, which appears to be the first step in HCBD metabolism. The mechanism of the conjugation at the olefinic double bond of HCBD is explained by an addition-elimination reaction. This pathway, which appears to lead to a destabilization of the HCBD molecule, could explain the distinct nephrotoxic effects of HCBD. |
