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• W4376617643 endingPage "915" @default.
• W4376617643 startingPage "900" @default.
• W4376617643 abstract "Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with the induction of oxidative stress and the progression of steatosis to steatohepatitis with fibrosis. It also disrupts metabolic pathways including one-carbon metabolism (OCM) and the transsulfuration pathway with possible consequences on glutathione (GSH) levels. In this study, complementary RNAseq and metabolomics data were integrated to examine the hepatic transsulfuration pathway and glutathione biosynthesis in mice following treatment with TCDD every 4 days for 28 days. TCDD dose-dependently repressed hepatic cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) mRNA and protein levels. Reduced CBS and CTH levels are also correlated with dose-dependent decreases in hepatic extract hydrogen sulfide (H2S). In contrast, cysteine levels increased consistent with the induction of Slc7a11, which encodes for the cystine/glutamate Xc- antiporter. Cotreatment of primary hepatocytes with sulfasalazine, a cystine/glutamate Xc- antiporter inhibitor, decreased labeled cysteine incorporation into GSH with a corresponding increase in TCDD cytotoxicity. Although reduced and oxidized GSH levels were unchanged following treatment due to the induction of GSH/GSSG efflux transporter by TCDD, the GSH:GSSG ratio decreased and global protein S-glutathionylation levels in liver extracts increased in response to oxidative stress along with the induction of glutamate-cysteine ligase catalytic subunit (Gclc), glutathione synthetase (Gss), glutathione disulfide reductase (Gsr), and glutathione transferase π (Gstp). Furthermore, levels of ophthalmic acid, a biomarker of oxidative stress indicating GSH consumption, were also increased. Collectively, the data suggest that increased cystine transport due to cystine/glutamate Xc- antiporter induction compensated for decreased cysteine production following repression of the transsulfuration pathway to support GSH synthesis in response to TCDD-induced oxidative stress." @default.
• W4376617643 created "2023-05-17" @default.
• W4376617643 creator A5009162439 @default.
• W4376617643 creator A5020069116 @default.
• W4376617643 creator A5021369775 @default.
• W4376617643 creator A5031282727 @default.
• W4376617643 creator A5070343943 @default.
• W4376617643 date "2023-05-15" @default.
• W4376617643 modified "2023-10-13" @default.
• W4376617643 title "Cystine/Glutamate Xc^– Antiporter Induction Compensates for Transsulfuration Pathway Repression by 2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin (TCDD) to Ensure Cysteine for Hepatic Glutathione Biosynthesis" @default.
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• W4376617643 doi "https://doi.org/10.1021/acs.chemrestox.3c00017" @default.
• W4376617643 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37184393" @default.
• W4376617643 hasPublicationYear "2023" @default.
• W4376617643 type Work @default.

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