Exposure to cis- and trans-regioisomers of S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-glutathione result in quantitatively and qualitatively different cellular effects in RPTEC/TERT1 cells

Bioactivation of trichloroethylene (TCE) via glutathione conjugation is associated with several adverse effects in the kidney and other extrahepatic tissues. Of the three regioisomeric conjugates formed, S-(1,2-trans-dichlor-ovinyl)-glutathione (1,2-trans-DCVG), S-(1,2-cis-dichlorovinyl)-glutathione and S-(2,2-dichlorovinyl)-gluta-thione, only 1,2-trans-DCVG and its corresponding cysteine-conjugate, 1,2-trans-DCVC, have been subject to extensive mechanistic studies. In the present study, the metabolism and cellular effects of 1,2-cis-DCVG, the major regioisomer formed by rat liver fractions, and 1,2-cis-DCVC were investigated for the first time using RPTEC/TERT1-cells as in vitro renal model. In contrast to 1,2-trans-DCVG/C, the cis-regioisomers showed minimal effects on cell viability and mitochondrial respiration. Transcriptomics analysis showed that both 1,2-cis-DCVC and 1,2-trans-DCVC caused Nrf2-mediated antioxidant responses, with 3 & mu;M as lowest effective con-centration. An ATF4-mediated integrated stress response and p53-mediated responses were observed starting from 30 & mu;M for 1,2-trans-DCVC and 125 & mu;M for 1,2-cis-DCVC. Comparison of the metabolism of the DCVG regioisomers by LC/MS showed comparable rates of processing to their corresponding DCVC. No detectable N-acetylation was observed in RPTEC/TERT1 cells. Instead, N-glutamylation of DCVC to form N-& gamma;-glutamyl-S-(dichlorovinyl)-L-cysteine was identified as a novel route of metabolism. The results suggest that 1,2-cis-DCVC may be of less toxicological concern for humans than 1,2-trans-DCVC, considering its lower intrinsic toxicity and lower rate of formation by human liver fractions.

Automated summary

Bioactivation of trichloroethylene (TCE) through glutathione conjugation can cause adverse effects in the kidney and other extrahepatic tissues. Among the three regioisomeric conjugates formed, only 1,2-trans-DCVG and its corresponding cysteine-conjugate have been extensively studied. This study investigates the metabolism and cellular effects of 1,2-cis-DCVG and 1,2-cis-DCVC for the first time, revealing lower toxicity and slower formation rate for 1,2-cis-DCVC compared to 1,2-trans-DCVC.