S-Adenosylmethionine Protects Hepatocytes against the Effects of Cytokines

Abstract

Cytokines are thought to play an important role in the hepatocellular dysfunction that occurs during sepsis. Some cytokines have been shown to increase lipogenesis and to induce toxicity in isolated hepatocytes. Oxygen free radicals have been implicated as mediators of some cytokine effects. In this study we investigate a possible protective action ofS-adenosyl-L- methionine against the toxic effects of cytokines on isolated hepatocytes. Isolated rat hepatocytes were precultured for 24 hr and then cultured for 1, 2, 3, 6, 12, or 24 hr in the presence or absence ofS-adenosyl-L-methionine (12 μmol/l) and/or either tumor necrosis factor (100, 200, or 500 ng/ml) or interleukin-1 (30, 60, or 120 IU/ml). Lactate dehydrogenase (media), and malondialdehyde, reduced glutathione, and the incorporation ofD-[U-14C]glucose into different lipid fractions (cells) were determined. Both cytokines significantly increased hepatocyte malondialdehyde content, lactate dehydrogenase release, and triacylglycerol synthesis. None of these effects were observed in the presence ofS-adenosyl-L-methionine. In addition,S-adenosyl-L-methionine was able to attenuate the decrease in phosphatidylcholine labeling also induced by both cytokines, and to prevent the increase in free fatty acid synthesis induced by tumor necrosis factor. Incubation in the presence ofS-adenosyl-L-methionine also increased hepatocyte glutathione content (7.1 ± 0.7, after 24 hr, vs 3.6 ± 0.3 nmole/mg protein,P< 0.01), and prevented the decrease in glutathione induced by tumor necrosis factor (5.4 ± 0.2 vs 2.1 ± 0.1 nmole/mg protein, 100 ng/ml TNFα at 24 hr,P< 0.01). Our results show thatS-adenosyl-L-methionine has a protective effect on hepatocytes against thein vitroeffect of cytokines.