Metabolism of the nephrotoxin dichloroacetylene by glutathione conjugation
The authors report the identification of S-(1,2-dichlorovinyl)glutathione (DCVG) as a product of the glutathione (GSH) dependent metabolism of DCA in vitro and the identification of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (N-Ac-DCVC) as a urinary metabolite of DNA in rats. Formation of DCVG from DCa, used a 1:1 complex with diethyl ether, in male rat liver and kidney subcellular fractions was dependent on time, native protein, and the presence of GSH. Initial reactions rates at 23 /degrees/C were determined as 2923 nmol/(min/times/mg) for kidney microsomes. With cytosol, DCVG formation rates were 705 nmol/(min/times/mg) (liver cytosol) and 129 nmol/(min/times/mg) (kidney cytosol). With liver microsomes, a K/sub M/ of 7.5 mM and a V/sub max/ of 5464 nmol/(min/times/mg) for GSH were obtained. The product DCVG, was definitively identified by /sup 1/H NMR spectrometry (400 MHz), mass spectrometry, and UV spectroscopy. N-Ac-DCVC was identified as a urinary metabolite from rats by GC/MS after esterification. Urine from male rats exposed to 36 /plus minus/ 5 ppm DCA for 1 h contained 10.7 ..mu..mol of N-Ac-DCVC as determined by HPLC analysis. Formation of DCVG, renal processing to S-(1,2-dichlorovinyl)-L-cysteine, and cleavage of this cysteine S-conjugate by cysteine S-conjugate ..beta..-lyase in the kidney with formation of reactive and mutagenic intermediates may account for DCA nephrotoxicity and nephrocarcinogenicity.
- Research Organization:
- Universitaet Wuerzburg (Germany, F.R.)
- OSTI ID:
- 6044118
- Journal Information:
- Chem. Res. Toxicol.; (United States), Vol. 2:1
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
CHLORINATED ALIPHATIC HYDROCARBONS
METABOLISM
CARCINOGENESIS
GLUTATHIONE
KIDNEYS
LIQUID COLUMN CHROMATOGRAPHY
METABOLITES
MICROSOMES
NMR SPECTRA
RATS
TIME DEPENDENCE
TOXICITY
ANIMALS
BODY
CELL CONSTITUENTS
CHROMATOGRAPHY
DRUGS
HALOGENATED ALIPHATIC HYDROCARBONS
MAMMALS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANOIDS
ORGANS
PATHOGENESIS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RODENTS
SEPARATION PROCESSES
SPECTRA
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology