In various experimental models, S-adenosylmethionine (SAMe) has been shown to reduce liver injury by preventing depletion of glutathione, one of the antioxidant systems that plays a critical role in ...defence against oxidative stress. On the other hand, alpha-tocopherol may be decreased in liver diseases, and treatment with this vitamin reduces liver injury in CCl(4)-treated rats. Since there is a close relationship among the different antioxidant systems (mainly glutathione, alpha-tocopherol and ascorbic acid), we have assessed whether, as well as restoring hepatic glutathione content, SAMe has any effect on liver alpha-tocopherol and ascorbic acid levels in CCl(4)-injured rats. Four groups of seven male Wistar rats treated for 9 weeks were studied: rats induced to cirrhosis with CCl(4), rats induced to cirrhosis plus SAMe administration (10 mg x kg(-1) x day(-1)) and their respective controls. Liver samples were obtained for measuring levels of glutathione, alpha-tocopherol, ascorbic acid and thiobarbituric acid-reactive substances (TBARS), and hydroxyproline concentration as an index of collagen content. The hydroxyproline content was higher in CCl(4)-injured rats than in the control group (4.4+/-1.8 and 1.1+/-0.3 micromol/g respectively; P<0.05). In CCl(4)-injured rats, SAMe administration decreased collagen content (2.7+/-1.0 microl/g; P<0.05) and TBARS, and corrected glutathione depletion. alpha-Tocopherol was significantly lower in CCl(4)-injured rats than in controls (17.3+/-4.9 and 23.0+/-4.0 micromol/g respectively; P<0.05). By contrast, alpha-tocopherol levels were similar (23.8+/-5.1 micromol/g) in CCl(4)-injured rats receiving SAMe and in controls. In CCl(4)-injured rats, liver ascorbic acid was decreased in comparison with controls (4.9+/-1.8 and 8.2+/-1.0 micromol/g respectively; P<0.05), levels which were not replenished by SAMe (4.6+/-0.4 micromol/g). In conclusion, SAMe not only decreases fibrosis and protects against hepatic glutathione depletion, but has a further antioxidant effect of preventing alpha-tocopherol depletion in CCl(4)-injured rats.
Because transcription factors NF-κB and activator protein-1 (AP-1) are known to regulate gene expression, we have analyzed
the role of acetaldehyde in the activation of NF-κB and AP-1 in HepG2 ...cells. Binding activity and transactivation of NF-κB
and AP-1 were determined by gel retardation assays and transfection of a luciferase reporter construct controlled by κB and
AP-1 binding sites, respectively. Acetaldehyde enhanced the DNA binding of NF-κB and AP-1 by 1 and 4 h, respectively, increasing
the κB- and AP-1-dependent luciferase expression. Supershift assays revealed the presence of NF-κB heterodimers p65/p50 and
p50/p52, whereas nuclear c-Jun levels correlated with the DNA binding of AP-1. The enhanced binding of NF-κB to DNA by acetaldehyde
in intact cells was accompanied by the proteolytic degradation of IκB-α. However, the addition of acetaldehyde to cytostolic
extracts from untreated Hep G2 cells did not affect the DNA binding of AP-1 but activated the NF-κB heterodimer p65/p50 in
the absence of IκB-α degradation. Preincubation of HepG2 cells with protein kinase C inhibitors abolished the enhanced DNA
binding of NF-κB and AP-1 caused by acetaldehyde. Hence, these findings uncover a previously unrecognized role for acetaldehyde
in the activation of NF-κB and AP-1, which may be of relevance in the alcohol-induced liver disease.
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