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- κ B) activity, and NF- κ 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 CCl 4 in mice. This injury was significantly inhibited by intravenous pretreatment of the mice with a water-soluble emulsion of α-tocopherol. Alpha-tocopherol treatment of the mice given the CCl 4 also reduced the NF- κ B binding to levels approaching those found in normal mice. In vitro treatment of a monocyte/macrophage cell line with CCl 4 led to enhanced NF- κ B binding and an increase in tumor necrosis factor-α (TNF-α) messenger RNA levels. Liver specimens taken from patients with acute fulminant hepatitis had markedly increased NF- κ B binding activity in comparison with the binding of normal livers. These data demonstrate that abolishing acute hepatic injury with α-tocopherol, a free radical scavenger, also eliminated increased NF- κ B binding. It is tempting to speculate that enhanced NF- κ B expression caused by free radical production/oxidative stress may modulate liver injury, perhaps through an effect on cytotoxic cytokine synthesis. (Hepatology 1995; 22:1474-1481).