title: Glutathione-deficient mice are susceptible to TCDD-Induced hepatocellular toxicity but resistant to steatosis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy,  University of Colorado Denver , Aurora, Colorado 80045, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Mansi
authors.initials: M
authors.lastname: Krishan
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004785:Environmental Pollutants / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency / Q000235:genetics; D005978:Glutathione / Q000172:deficiency*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione