Enzymatic Conjugation of Hexachloro-1,3-Butadiene with Glutathione. Formation of 1-(Glutathion- S-yl)-1,2,3,4,4- pentachlorobuta-1,3-diene and1,4-bis(glutathion- S-yl)-1,2,3,4-tetrach lorobuta-1,3-diene. (Reannouncement with New Availability Information).

摘要

The glutathione-dependent metabolism of the nephrotoxin and nephrocarcinogen hexachloro-1,3-butadiene (HCBD) was investigated in subcellular fractions from rat livers and kidneys. HCBD was metabolized by hepatic glutathione S-transferases to (E)- and (Z)-1-(glutathion-S- yl)-pentachlorobuta-1,3-diene (GPCB) in a ratio of 20:1, which were identified by secondary ion MS and by GC-MS after acid hydrolysis. The formation of GPCB was dependent on time and on protein and glutathione concentrations. Microsomal glutathione S-transferases from rat livers catalyzed GPCB formation more efficiently than did cytosolic glutathione S-transferases; very low rates of GPCB formation were observed in kidney subcellular fractions. GPCB is also a substrate for glutathione S-transferases and is metabolized to a diglutathione conjugate, which was identified by secondary ion MS and (13)C NMR spectrometry as 1,4-bis(glutathion- S-yl)-1,2,3,4-tetrac hlorobuta-1,3-diene (BTCB). BTCB formation from GPCB was dependent on time and on protein, glutathione, and GPCB concentrations. Hepatic cytosol catalyzed BTCB formation more efficiently than did hepatic microsomes; significant amounts of BTCB were also formed in kidney cytosol. Hepatic formation of glutathione S-conjugates, translocation of the S-conjugates to the kidney, and renalprocessing to form reactive intermediates may be the cause of HCBD-induced nephrotoxicity and, perhaps, nephrocarcinogenicity. The halogenated olefin HCBD is a selective nephrotoxin and a potent nephrocarcinogen. (Author)