S-Adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte growth, death, and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of all forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and hepatocellular carcinoma. However, impaired SAMe metabolism, which occurs in patients with mutations of glycine N-methyltransferase (GNMT), can also lead to liver injury. This suggest that hepatic SAMe level needs to be maintained within a certain range, and deficiency or excess can both lead to abnormality. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also show it is effective in patients with cholestatic liver diseases. Recent data show that exogenous SAMe can regulate hepatocyte growth and death, independent of its role as a methyl donor. This raises the question of its mechanism of action when used pharmacologically. Indeed, many of its actions can be recapitulated by methylthioadenosine (MTA), a by-product of SAMe that is not a methyl donor. A better understanding of why liver injury occurs when SAMe homeostasis is perturbed and mechanisms of action of pharmacologic doses of SAMe are essential in defining which patients will benefit from its use. (HEPATOLOGY 2007;45: 1306-1312.)
SAMe: Historical Perspective
Although S-adenosylmethionine (SAMe, also abbreviated as AdoMet and SAM) 1 was discovered approximately 50 years ago, its story began in 1890 with Wilhelm His. When he fed pyridine to dogs, he was able to isolate N-methylpyridine from the urine and emphasized the need to demonstrate both the origin of the methyl group as well as the mechanism of its addition to the pyridine. 2 Both questions were addressed by Vincent du Vigneaud, who, during the late 1930s, demonstrated that the sulfur atom of methionine was transferred to cysteine through the "transsulfuration" pathway, that is, the change of methyl groups from methionine, choline, betaine, and creatine. In 1951, Cantoni demonstrated that a liver homogenate supplemented with adenosine triphosphate (ATP) and methionine converted nicotinamide to N-methylnicotinamide. Two years later, he established that methionine and ATP reacted to form a product, which he originally named "active methionine," capable of transferring its methyl group to nicotinamide or creatine in the absence of ATP. After determination of its structure, he called it SAMe (Fig. ). Subsequently, Cantoni and his colleagues discovered methionine adenosyltransferase (MAT, the enzyme that synthesizes SAMe), S-adenosylhomocysteine (SAH, the product of the transmethylation reactions), and SAH-hydrolase [the enzyme that converts SAH to homocysteine (Hcy) and adenosine]. At about the same time, Benett discovered that folate and vitamin B 12 could replace choline as a source of