S-adenosylmethionine (
AdoMet, also known
as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of
AdoMet requires the
enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic
liver disease have reduced MAT activity and
AdoMet levels. Mice lacking Mat1a have reduced hepatic
AdoMet levels and develop oxidative stress,
steatohepatitis, and
hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic
AdoMet level is excessive chronically. This can result from inactive mutation of the
enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver
transaminases, and Gnmt knockout mice develop liver injury,
fibrosis, and HCC. Thus a normal hepatic
AdoMet level is necessary to maintain liver health and prevent injury and HCC.
AdoMet is effective in
cholestasis of pregnancy, and its role in other human
liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of
cancer as well.