Vitamin E therapy of acute CCl4-induced hepatic injury in mice is associated with inhibition of nuclear factor kappa B binding

Abstract

Oxidative stress, with reactive oxygen intermediate formation, may represent a common mechanism by which liver injury is induced by diverse etiologies. Oxidative stress enhances nuclear factor kappa B (NF-kappa B) activity, and NF-kappa B activity has been shown to enhance the expression of cytotoxic cytokines. Acute hepatic injury caused by reactive oxygen intermediate production was induced by an intraperitoneal injection of CCl4 in mice. This injury was significantly inhibited by intravenous pretreatment of the mice with a water-soluble emulsion of alpha-tocopherol. Alpha-tocopherol treatment of the mice given the CCl4 also reduced the NF-kappa B binding to levels approaching those found in normal mice. In vitro treatment of a monocyte/macrophage cell line with CCl4 led to enhanced NF-kappa B binding and an increase in tumor necrosis factor-alpha (TNF-alpha) messenger RNA levels. Liver specimens taken from patients with acute fulminant hepatitis had markedly increased NF-kappa B binding activity in comparison with the binding of normal livers. These data demonstrate that abolishing acute hepatic injury with alpha-tocopherol, a free radical scavenger, also eliminated increased NF-kappa B binding. It is tempting to speculate that enhanced NF-kappa B expression caused by free radical production/oxidative stress may modulate liver injury, perhaps through an effect on cytotoxic cytokine synthesis.

Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice

“…The generated trichloromethyl free radical causes liver cell necrosis as well as destruction of the extracellular matrix, through lipid peroxidation of membranes [31,33]. In addition to its cytotoxic effects, CCl 4 activates several transcription factors [31], including NF-B [34], a transcription factor complex essentially involved in several inflammatory cytokines, including IL-6 [35]. IL-6 mRNA as well as immunoreactive IL-6 protein was detected in liver after repeated injection with CCl 4 , although IL-6 was not detected in plasma.…”

Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat

“…25 Preparation of Cytosolic and Nuclear Extracts. The livers were fractionated as described previously 26 with some modification. One gram of the liver tissue was homogenized using a Dounce homogenizer (Lab Glass, Vineland, NJ) in 5-mL buffer (0.32 mol/L sucrose, 50 mmol/L Tris-HC1 [pH 7.5], 25 mmol/L KC1, 5 mmol/L MgC1 2 , 0.5 mmol/L phenylmethylsulfonyl fluoride, 10 µg/mL aprotinin, 10 µg/mL tosyllysylchloromethyl ketone [TLCK], 10 µg/mL tosylphenylalonylchloromethyl ketone [TPCK]) and centrifuged at 600g at 4°C for 10 minutes.…”

N-acetylcysteine attenuates alcohol-induced oxidative stress in the rat

“…Oxidative damage correlates with the amount of ethanol consumed [8] . Antioxidants such as vitamin E have been suggested as therapeutic options in acute and chronic liver diseases [9,10] . Nacetylcysteine (NAC) exerts a strong antioxidant activity, and is the treatment of choice in acetaminophen intoxication.…”