Free Radical Injury and Liver Tumor Promotion

Abstract

ABSTRACT-One of the underlying mechanisms of tumor promotion both in the skin and liver involves free radical mediated injury to informational macromolecules of target cells. A choline-deficient (CD) diet, which is an efficient liver tumor promoter, induces peroxidative damage of liver cell membrane lipids. By modifying components of a CD diet, we have shown that the efficacy of the promotion is correlated with the extent of lipid peroxidation. The substitution of fats in a CD diet with predominantly polyunsaturated fat and the addition of methapyrilene to a CD diet enhances membrane lipid peroxidation and the promoting effects. An antioxidant (BHT) and hypolipidemic peroxisome proliferators (BR93 1 and DEHP) suppress both of these erects. Contrary to these findings, phenobarbital did not induce membrane lipid peroxidation, and its addition to a CD diet inhibited the diet-induced lipid peroxidation, though such a combination exerted a stronger promoting action. Thus, a CD diet and phenobarbital exert their promoting actions through different mechanisms. The consequence of membrane lipid peroxidation in the liver cells induced by a CD diet may be multiple. Our rccent study of surface membrane insulin receptors of liver cells of rats fed a CD diet showed a decrease in number and an enhanced binding affinity leading to altered responsiveness of liver cells to insulin mediated glycogen synthesis. It is suggested that CD diet-induced lipid peroxidation leads to functional alterations of membrane receptors involved in cell growth control and may thereby exert its promoting action.

Discovery and analysis of hepatocellular carcinoma genes using cDNA microarrays

“…Dramatic up-regulation was observed for the detoxifying genes of the peroxisome and a number of catabolic enzymes. Though these enzymes play an important role in the oxidative breakdown of toxic compounds under normal conditions, unusually high levels of catalase and other enzymes may lead to the free radical injury of intracellular macromolecules, a process that has been shown to promote hepatocellular carcinogenesis (Perera et al 1987). Mutations in the gene encoding phytanoyl-CoA alpha-hydroxylase (PAHX) are believed to cause Refsum disease (Mihalik et al 1997), establishing a direct link between the activity of one of these genes and a human disease.…”

Biological Basis of Differential Susceptibility to Hepatocarcinogenesis among Mouse Strains

“…Generation of reactive oxygen species as a consequence of futile cycling of P450s 155 is capable of producing tissue necrosis and mutations that would favor development of hepatic neoplasia. Reactive oxygen species can lead to lipid peroxidative damage to hepatocyte cell membranes and may then cause functional alterations in membrane receptors that in turn exert liver promoting action 156 . Reactive oxygen species can also modulate gene expression and lead to altered regulation of growth factors that favor tumor promotion and progression 154 .…”

Methyl-group donors cannot prevent apoptotic death of rat hepatocytes induced by choline-deficiency

“…Livers from rats fed diets devoid of choline (1) accumulated triacylglycerol and 1,2-sn-diacylglycerol with sustained activation of protein kinase C [da Costa et al, 1993, (2) became depleted of labile methyl groups resulting in DNA hypomethylation [Christman, 1995a,b;Dizik et al, 1991;Locker et al, 1986;Wainfan and Poirier, 1992], (3) accumulated reactive oxygen species with associated damage to DNA [Banni et al, 1990;Perera et al, 1987], (4) had increased liver cell death and regeneration [Chandar et al, 1987;Takahashi et al, 1979], and (5) developed hepatocellular carcinoma Ghoshal and Farber, 1984;Mikol et al, 1983;Newberne and Rogers, 1986]. We found that the increased rate of cell death that occurs in early choline-deficiency is due to apoptosis [Albright et al, 1996].…”