Metabolism of hexachloro-1,3-butadiene in mice: in vivo and in vitro evidence for activation by glutathione conjugation.
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 subcellular fractions from mouse kidney was very limited. Oxidative metabolism of HCBD by cytochrome P-450 could not be demonstrated. 3. Cysteine conjugate beta-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 beta-lyase-catalysed formation of reactive intermediates, accounts for the organ specific toxicity of HCBD in mice.
Dekant
W
W
Institut für Toxikologie, Universität Würzburg, FR Germany.
Schrenk
D
D
Vamvakas
S
S
Henschler
D
D
D000818:Animals; D001711:Biotransformation; D002070:Butadienes / Q000378:metabolism / Q000493:pharmacokinetics*; D013437:Carbon-Sulfur Lyases; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005243:Feces / Q000032:analysis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008190:Lyases / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism
D002070:Butadienes; D003577:Cytochrome P-450 Enzyme System; C001335:hexachlorobutadiene; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D005978:Glutathione