Free Radicals and Liver Injury

In the field of free radicals and liver injury there is a vast body of work concerning a group of compounds that have proven to be of great value as experimental models but are of little clinical significance. The most frequently used compounds are quinones (particularly menadione), paraquat and diquat, bromobenzene, and organic hydroperoxides, particularly cumene hydroperoxide and r-butyl hydroperoxide (see Poli et al., 1989b). 

Esterbauer, LI. (1985). Lipid peroxidation products formation, chemical properties and biological activation. In Free Radicals in Liver Injury (eds. G. Poli, K. Cheeseman, M.U. Dianzani and T. Slater) pp. 29-47, IRL Press, Oxford. 

Recknagel, R.O. and Glende, E.A. (1992). Calcium, phospholipase Az and eicosanoids in toxigenic liver cell injury. In Free Radicals and Liver (eds. G. Csomos and J. Feher) pp. 43-62. Springer-Verlag, Berlin. 

A number of early in vitro studies demonstrated a considerable role of free radicals in liver injury (see, for example, Proceedings of International Meeting on Free Radicals in Liver Injury [341]). Later on, it was shown that chronic inflammation in the liver-induced oxidative DNA damage stimulated chronic active hepatitis and increased the risk of hepatocarcinogenesis [342,343]. Farinati et al. [344] showed that 8-OHdG content increased in circulating leukocytes of patients with chronic hepatitis C virus (HCV) infection. DNA oxidative damage is supposedly an early event of HCV-related hepatitis. The formation of isoprostanes in the liver of carbon tetrachloride-treated rats can be suppressed by the administration of vitamin E [345],... 

Willson, R. L. Free radicals and tissue damage Mechanistic evidence from radiation studies. In Biochemical Mechanisms of Liver Injury (Slater, T. F., ed.), London-New York-San Francisco, Academic Press, 1978, pp. 123-224... 

Pharmacology In vitro studies show that milk thistle reduces lipid peroxidation, scavenges free radicals, enhances superoxide dismutase, inhibits formation of leukotrienes, and increases hepatocyte RNA polymerase activity. In animal models, milk thistle protects against liver injury caused by alcohol, acetaminophen, and amanita mushrooms. The outcomes of clinical trials in patients with liver disease caused by alcohol have been mixed. In viral hepatitis and liver injury caused by amanita mushrooms, results of clinical trials have been mainly favorable. A commercial preparation of silybin (an isomer of silymarin) is available in some countries as an antidote to Amanita phalloides mushroom poisoning. 

Chemiluminescence has been used to show increased free-radical production in I/R injury in isolated hepatocytes and in isolated rat livers (Caraceni et al., 1992 Nunes et al., 1992). Studies in isolated rat liver have shown that ischaemia results in increased conversion of... 

The production of free radicals has been implicated in the mechanism of liver injury due to a number of drugs and toxins. These include adtiamycin (Pritsos et al., 1992), halothane (Neuberger and Williams, 1984), phenobar-bital and thiopental (Kanazawa and Ashida, 1991), carbon tetrachloride (Williams and Burk, 1990), 1,1,2,2-tetrachloroethane (Paolini aal., 1992), and paraquat and related bipyridylium compounds (Togashi a al., 1990 De Gray etal., 1991 Kanazawa and Ashida, 1991 Petty etal., 1992). 

Adkinson, D., Hollwarth, M.E., Benoit, J.N., Parks, D.A., McCord, J.M. and Granger, D.N. (1986). Role of free radicals in ischaemia-reperfusion injury to the liver. Acta Physiol. Scand. 548 (Suppl.), 101-107. 

Marubayashi, S., Dohi, K., Ochi, K. and Kawasaki, T. (1986). Role of free radicals in ischaemic rat liver cell injury prevention of damagy by a-tocopherol administration. Surgery 99, 184-199. 

Williams, A.T. and Burk, R.F. (1990). Carbon tetrachloride hepatotoxicity, an example of free radical-mediated injury. Semin. Liver Dis. 10, 279-284. 

A particular instance of iron overload being associated with liver injury, with free radicals again being implicated, is the hepatic porphyria and hepatocarcinoma induced by polyhalogenated aromatic chemicals. This is described separately below. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

As stated at the beginning of this article, the liver is the most intensively studied animal tissue in biochemistry. In the context of the role of free radicals in human diseases, the liver is not obviously at centre stage, since heart disease and cancer are more important in the industrialized world than, for example, cirrhosis. Free-radical biochemistry of the liver will remain a fertile area of work, however, not least because so many original ideas and techniques are developed there and then applied to the study of other tissues. The increasing use of liver transplantation, following the acceptance of kidney and heart transplants as almost routine, will surely increase the interest in the study of ischaemia-reperfusion injury in... 

Poli, G., Cheeseman, K.H., Dianzani, M.U. and Slater, T.F. (1989b). Free Radicals in the Pathogenesis of Liver Injury , Pergamon Press, Oxford. 

No information is available on the adverse health effects of hexachloroethane in humans. Animal studies revealed that hexachloroethane primarily causes liver and kidney toxicity. Effects on the nervous system and lungs have also been reported. The mechanism by which these effects are mediated is not well characterized. Reductive metabolism by cytochrome P-450 and production of a free radical intermediate have been suggested as factors in hexachloroethane-induced hepatotoxicity (Nastainczyk et al. 1982a Thompson et al. 1984 Town and Leibman 1984). Accordingly, one possible approach may be to reduce free radical injury. To that end, oral administration of N-acetylcysteine can be used as a means of reducing free radical injury. Also, oral administration of vitamin E and vitamin C may be of value since they are free radical scavengers. 

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