Metabolism of hexachloro-1,3-butadiene in mice: in vivo and in vitro evidence for activation by glutathione conjugation

Abstract

1. The metabolism of ¹⁴C-hexachloro-1,3-butadiene (HCBD) was studied in mice and in subcellular fractions from mouse liver and kidney.

2. In the presence of glutathione (GSH), liver microsomes and cytosol transformed HCBD to S-(pentachlorobutadienyl)glutathione (PCBG). PCBG formation in sub-cellular fractions from mouse kidney was very limited. Oxidative metabolism of HCBD by cytochrome P-450 could not be demonstrated.

3. Cysteine conjugate β-lyase was present in mitochondria and cytosol from mouse liver and kidney.

4. After an oral dose of 30 mg/kg ¹⁴C-HCBD, mice eliminated 67˙5-76˙7% of dose in faeces; urinary elimination accounted for 6˙6-7˙6%.

5. Metabolites of HCBD identified are: S-(pentachlorobutadienyl)glutathione in faeces; S-(pentachlorobutadienyl)-L-cysteine, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine and 1,1,2,3-tetrachlorobutenoic acid in urine.

6. The results suggest that conjugation of HCBD with GSH in liver, followed by renal processing of the glutathione S-conjugates and β-lyase-catalysed formation of reactive intermediates, accounts for the organ specific toxicity of HCBD in mice.