Enzymatic conjugation of hexachloro-1,3-butadiene with glutathione. Formation of 1-(glutathion-S-yl)-1,2,3,4,4-pentachlorobuta-1,3-diene and 1,4-bis(glutathion-S-yl)-1,2,3,4-tetrachlorobuta-1,3-diene
The glutathione-dependent metabolism of the nephrotoxin and nephrocarcinogen hexachloro-1,3-butadiene (HCBD) was investigated in subcellular fractions from rat liver and kidney. 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 liver 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 /sup 13/C NMR spectrometry as 1,4-bis(glutathion-S-yl)-1,2,3,4-tetrachlorobuta-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 renal processing to form reactive intermediates may be the cause of HCBD-induced nephrotoxicity and, perhaps, nephrocarcinogenicity.
- Research Organization:
- Univ. of Rochester, NY (USA)
- OSTI ID:
- 6071406
- Journal Information:
- Drug Metab. Dispos.; (United States), Vol. 16:5
- Country of Publication:
- United States
- Language:
- English
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CHLORINATED ALIPHATIC HYDROCARBONS
METABOLISM
TRANSFERASES
ENZYME ACTIVITY
ACID HYDROLYSIS
CARBON 13
GAS CHROMATOGRAPHY
GLUTATHIONE
KIDNEYS
LIVER
MASS SPECTROSCOPY
MICROSOMES
NMR SPECTRA
NUCLEAR MAGNETIC RESONANCE
RATS
TIME DEPENDENCE
ANIMALS
BODY
CARBON ISOTOPES
CELL CONSTITUENTS
CHEMICAL REACTIONS
CHROMATOGRAPHY
DECOMPOSITION
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GLANDS
HALOGENATED ALIPHATIC HYDROCARBONS
HYDROLYSIS
ISOTOPES
LIGHT NUCLEI
LYSIS
MAGNETIC RESONANCE
MAMMALS
NUCLEI
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANOIDS
ORGANS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESONANCE
RODENTS
SEPARATION PROCESSES
SOLVOLYSIS
SPECTRA
SPECTROSCOPY
STABLE ISOTOPES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology