Role of microsomal and cytosolic glutathione S-transferase in the conjugation of hexachloro-1:3-butadiene and its possible relevance to toxicity

C. R. Wolf, P. N. Berry, J. A. Nash, T. Green, E. A. Lock

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Abstract

The mechanism of hexachloro-1:3-butadiene (HCBD)-induced glutathione depletion in male and female rats has been 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 is 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 thin-layer chromatography and mass spectral analysis strongly indicates the structure to be as 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 fraction but at a slower rate than in liver fractions. It is suggested that 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.

Original languageEnglish
Pages (from-to)202-208
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume228
Issue number1
Publication statusPublished - 15 Mar 1984

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