Title: Glutathione-deficient mice are susceptible to TCDD-Induced hepatocellular toxicity but resistant to steatosis.

Authors: Chen, Ying; Krishan, Mansi; Nebert, Daniel W; Shertzer, Howard G

Published In Chem Res Toxicol, (2012 Jan 13)

Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) generates both hepatocellular injury and steatosis, processes that involve oxidative stress. Herein, we evaluated the role of the antioxidant glutathione (GSH) in TCDD-induced hepatotoxicity. Glutamate-cysteine ligase (GCL), comprising catalytic (GCLC) and modifier (GCLM) subunits, is rate limiting in de novo GSH biosynthesis; GCLM maintains GSH homeostasis by optimizing the catalytic efficiency of GCL holoenzyme. Gclm(-/-) transgenic mice exhibit 10-20% of normal tissue GSH levels. Gclm(-/-) and Gclm(+/+) wild-type (WT) female mice received TCDD for 3 consecutive days and were then examined 21 days later. As compared with WT littermates, Gclm(-/-) mice were more sensitive to TCDD-induced hepatocellular toxicity, exhibiting lower reduction potentials for GSH, lower ATP levels, and elevated levels of plasma glutamic oxaloacetic transaminase (GOT) and γ-glutamyl transferase (GGT). However, the histopathology showed that TCDD-mediated steatosis, which occurs in WT mice, was absent in Gclm(-/-) mice. This finding was consistent with cDNA microarray expression analysis, revealing striking deficiencies in lipid biosynthesis pathways in Gclm(-/-) mice; qrt-PCR analysis confirmed that Gclm(-/-) mice are deficient in expression of several lipid metabolism genes including Srebp2, Elovl6, Fasn, Scd1/2, Ppargc1a, and Ppara. We suggest that whereas GSH protects against TCDD-mediated hepatocellular damage, GSH deficiency confers resistance to TCDD-induced steatosis due to impaired lipid metabolism.

PubMed ID: 22082335

MeSH Terms: Animals; Aspartate Aminotransferases/blood; Environmental Pollutants/toxicity*; Fatty Liver/chemically induced; Fatty Liver/metabolism*; Fatty Liver/pathology; Female; Gene Expression Regulation/drug effects; Glutamate-Cysteine Ligase/deficiency; Glutamate-Cysteine Ligase/genetics; Glutathione/deficiency*; Lipid Metabolism/drug effects*; Liver/drug effects; Liver/metabolism; Liver/pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Oligonucleotide Array Sequence Analysis; Polychlorinated Dibenzodioxins/toxicity*; Reverse Transcriptase Polymerase Chain Reaction; gamma-Glutamyltransferase/blood