Glutathione-Deficient Mice Are Susceptible to TCDD-Induced Hepatocellular Toxicity but Resistant to Steatosis

Abstract

2,3,7,8-Tetrachlorodibenzo-<i>p</i>-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. <i>Gclm­(−/−)</i> transgenic mice exhibit 10–20% of normal tissue GSH levels. <i>Gclm­(−/−)</i> and <i>Gclm­(+/+)</i> wild-type (WT) female mice received TCDD for 3 consecutive days and were then examined 21 days later. As compared with WT littermates, <i>Gclm­(−/−)</i> 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 <i>Gclm­(−/−)</i> mice. This finding was consistent with cDNA microarray expression analysis, revealing striking deficiencies in lipid biosynthesis pathways in <i>Gclm­(−/−)</i> mice; qrt-PCR analysis confirmed that <i>Gclm­(−/−)</i> mice are deficient in expression of several lipid metabolism genes including <i>Srebp2</i>, <i>Elovl6</i>, <i>Fasn, Scd1/2</i>, <i>Ppargc1a</i>, and <i>Ppara</i>. We suggest that whereas GSH protects against TCDD-mediated hepatocellular damage, GSH deficiency confers resistance to TCDD-induced steatosis due to impaired lipid metabolism