Bioactivation of trichloroethylene to three regioisomeric glutathione conjugates by liver fractions and recombinant human glutathione transferases:Species differences and implications for human risk assessment

Autor: Jan N. M. Commandeur, Paul Jennings, Liliana Capinha
Přispěvatelé: Molecular and Computational Toxicology, AIMMS
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Capinha, L, Jennings, P & Commandeur, J N M 2021, ' Bioactivation of trichloroethylene to three regioisomeric glutathione conjugates by liver fractions and recombinant human glutathione transferases : Species differences and implications for human risk assessment ', Toxicology Letters, vol. 341, pp. 94-106 . https://doi.org/10.1016/j.toxlet.2021.01.021
Toxicology Letters
Toxicology Letters, 341, 94-106. Elsevier BV
ISSN: 0378-4274
Popis: Enzymatic conjugation of glutathione (GSH) to trichloroethylene (TCE) followed by catabolism to the corresponding cysteine-conjugate, S-(dichlorovinyl)-L-cysteine (DCVC), and subsequent bioactivation by renal cysteine conjugate beta-lyases is considered to play an important role in the nephrotoxic effects observed in TCE-exposed rat and human. In this study, it is shown for the first time that three regioisomers of GSH-conjugates of TCE are formed by rat and human liver fractions, namely S-(1,2-trans-dichlorovinyl)-glutathione (1,2-trans-DCVG), S-(1,2-cis-dichlorovinyl)-glutathione (1,2-cis-DCVG) and S-(2,2-dichlorovinyl)-glutathione (2,2-DCVG). In incubations of TCE with rat liver fractions their amounts decreased in order of 1,2-cis-DCVG > 1,2-trans-DCVG > 2,2-DCVG. Human liver cytosol showed a more than 10-fold lower activity of GSH-conjugation, with amounts of regioisomers decreasing in order 2,2-DCVG > 1,2-trans-DCVG > 1,2-cis-DCVG. Incubations with recombinant human GSTs suggest that GSTA1-1 and GSTA2-2 play the most important role in human liver cytosol. GSTP1-1, which produces regioisomers in order 1,2-trans-DCVG > 2,2-cis-DCVG > 1,2-cis-DCVG, is likely to contribute to extrahepatic GSH-conjugation of TCE. Analysis of the products formed by a beta-lyase mimetic model showed that both 1,2-trans-DCVC and 1,2-cis-DCVC are converted to reactive products that form cross-links between the model nucleophile 4-(4-nitrobenzyl)-pyridine (NBP) and thiol-species. No NBP-alkylation was observed with 2,2-DCVC corresponding to its low cytotoxicity and mutagenicity. The lower activity of GSH-conjugation of TCE by human liver fractions, in combination with the lower fraction of potential nephrotoxic and mutagenic 1,2-DCVG-isomers, suggest that humans are at much lower risk for TCE-associated nephrotoxic effects than rats.
Databáze: OpenAIRE
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