S‐adenosylhomocysteine sensitizes to TNF‐α hepatotoxicity in mice and liver cells: A possible etiological factor in alcoholic liver disease

In alcoholic liver disease, tumor necrosis factor‐α (TNFα) is a critical effector molecule, and abnormal methionine metabolism is a fundamental acquired metabolic abnormality. Although hepatocytes are resistant to TNFα‐induced killing under normal circumstances, previous studies have shown that primary hepatocytes from rats chronically fed alcohol have increased TNFα cytotoxicity. Therefore, there must be mechanisms by which chronic alcohol exposure “sensitizes” to TNFα hepatotoxicity. S‐adenosylhomocysteine (SAH) is product of methionine in transsulfuration pathway and a potent competitive inhibitor of most methyltransferases. In this study, we investigated the effects of increased SAH levels on TNFα hepatotoxicity. Our results demonstrated that chronic alcohol consumption in mice not only decreased hepatic S‐adenosylmethionine levels but also increased hepatic SAH levels, which resulted in a significantly decreased S‐adenosylmethionine‐to‐SAH ratio. This was associated with significant increases in hepatic TNFα levels, caspase‐8 activity, and cell death. In vitro studies demonstrated that SAH‐enhancing agents sensitized hepatocytes to TNFα killing, and the death was associated with increased caspase‐8 activity, which was blocked by a caspase‐8 inhibitor. In addition, increased intracellular SAH levels had no effect on nuclear factor κB activity induced by TNFα. In conclusion, these results provide a new link between abnormal methionine metabolism and abnormal TNFα metabolism in alcoholic liver disease. Increased SAH is a potent and clinically relevant sensitizer to TNFα hepatotoxicity. These data further support improving the S‐adenosylmethionine‐to‐SAH ratio and removal of intracellular SAH as potential therapeutic options in alcoholic liver disease. Supplementary material for this article can be found on the HEPATOLOGYwebsite (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2004;40:989–997.)