1 research outputs found
Glutathione-Deficient Mice Are Susceptible to TCDD-Induced Hepatocellular Toxicity but Resistant to Steatosis
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>GclmÂ(−/−)</i> transgenic mice exhibit 10–20%
of normal tissue GSH levels. <i>GclmÂ(−/−)</i> and <i>GclmÂ(+/+)</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>GclmÂ(−/−)</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>GclmÂ(−/−)</i> mice. This finding
was consistent with cDNA microarray expression analysis, revealing
striking deficiencies in lipid biosynthesis pathways in <i>GclmÂ(−/−)</i> mice; qrt-PCR analysis confirmed that <i>GclmÂ(−/−)</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