ROLE OF MICROSOMAL AND CYTOSOLIC GLUTATHIONE S-TRANSFERASES IN THE CONJUGATION OF HEXACHLORO-1-3-BUTADIENE AND ITS POSSIBLE RELEVANCE TO TOXICITY
- 1 January 1984
- journal article
- research article
- Vol. 228 (1), 202-208
Abstract
The mechanism of hexachloro-1:3-butadiene (HCBD)-induced glutathione depletion in male and female rats was investigated in rat liver and kidney preparations in vitro in order to characterize the enzymes involved and to study the relationship between this effect and the nephrotoxic action of this compound. HCBD caused a marked reduction in glutathione concentration when incubated with male or female hepatic microsomal or cytosolic fractions fortified with glutathione. In contrast with that reported for other halo-olefin''s, the depletion of glutathione in the microsomal fraction was not related to the formation of metabolites via cytochrome P-450. The microsomal rate of depletion appeared to be due to a direct reaction catalyzed by a microsomal glutathione S-transferase. A glutathione adduct of HCBD was isolated by TLC and mass spectral analysis strongly indicated the structure to be S-(1,1,2,3,4-pentachloro-1,3-butadienyl)glutathione, confirming a direct substitution reaction without prior oxidation. This conjugate was formed at a faster rate by the hepatic microsomal fraction than by the cytosolic fraction suggesting a major role for the microsomal glutathione S-transferases in the disposition of this compound. A second more polar glutathione-dependent adduct which may be a double conjugate was formed with cytosol. Glutathione adducts were also formed by male and female kidney cytosol and microsomal fractions but at a slower rate than in liver fractions. The glutathione conjugate of HCBD may be converted to the cysteine derivative, the structure of which is similar to that of S-dichloro-vinyl-L-cysteine and therefore may be nephrotoxic by a similar mechanism.This publication has 11 references indexed in Scilit:
- The nephrotoxicity of hexachloro-1:3-butadiene in the rat: Studies of organic anion and cation transport in renal slices and the effect of monooxygenase inducersToxicology and Applied Pharmacology, 1982
- MICROSOMAL GLUTATHIONE S-TRANSFERASE - PURIFICATION, INITIAL CHARACTERIZATION AND DEMONSTRATION THAT IT IS NOT IDENTICAL TO THE CYTOSOLIC GLUTATHIONE S-TRANSFERASE-A, S-TRANSFERASE-B AND S-TRANSFERASE-C1982
- Hepatic and renal nonprotein sulfhydryl concentration following toxic doses of hexachloro-1,3-butadiene in the rat: The effect of Aroclor 1254, phenobarbitone, or SKF 525A treatmentToxicology and Applied Pharmacology, 1981
- Characterization of Rat‐Liver Microsomal Glutathione S‐Transferase ActivityEuropean Journal of Biochemistry, 1980
- The acute toxic effects of hexachloro-1 : 3-butadiene on the rat kidneyArchives of Toxicology, 1979
- Effects of hexachlorobutadiene (HCBD) on renal function and renal organic ion transport in the ratToxicology, 1979
- Activation of microsomal glutathione S-transferase activity by sulfhydryl reagentsBiochemical and Biophysical Research Communications, 1979
- Cleavage of S-(1,2-dichlorovinyl)-l-cysteine by an enzyme of bovine originArchives of Biochemistry and Biophysics, 1965
- The formation of mercapturic acids. 2. The possible role of glutathionaseBiochemical Journal, 1959
- PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENTJournal of Biological Chemistry, 1951