SAMe

SAMe is the principal methyl donor and the precursor of amino propyl groups and of glutathione in the liver; it also regulates the activities of various enzymes. SAMe is formed by activation of dietary methionine by ATP in are action catalyzed by methionine adenosyltransferase. SAMe contains a high-energy sulfonium ion, which activates each of the attached carbons toward nucleophilic attack and confers on SAMe the ability to participate in 3 major types of reactions: Transmethylation, Transsulfuration and Aminopropylation.

In transmethylation reactions, SAMe serves primarily as the universal methyl donor to a variety of acceptors including nucleic acids, proteins, phospholipids, and biologic amines.Although a specific enzyme catalyzes each of these reactions, the common product of all methylation reactions is S-adenosylhomocysteine (SAH).
Most of SAMe-dependent methylation reactions are strongly inhibited by increases in SAH and decreases in SAMe concentrations. Therefore, the removal of SAH is essential. SAH is hydrolyzed to homocysteine and adenosine by SAH hydrolase. This hydrolysis is a reversible reaction that favors the synthesis of SAH. In vivo, the reaction proceeds in the direction of hydrolysis only if the products, adenosine and homocysteine, are removed rapidly. There are 2 pathways that metabolize homocysteine: remethylation and transsulfuration.
In the remethylation pathway, homocysteine acquires a methyl group from N-5-methyltetrahydrofolate (in humans) or from betaine (only in rodents) to regenerate methionine. The reaction with N-5-methyltetrahydrofolate occurs in all tissues and is dependent on vitamin B12. In the transsulfuration pathway, homocysteine condenses with serine to form cystathionine, an irreversible reaction catalyzed by cystathionine-synthase in the presence of vitamin B6 as a cofactor. Cystathionine, in turn, is hydrolyzed by cystathionase to form cysteine and ketobutyrate. Cysteine reacts with glutamate and glycine through 2 consecutive reactions to form the tripeptide glutathione, which is the primary endogenous cellular antioxidant defense molecule in mammalian organisms.
Transfer of the propylamine group of SAMe for the synthesis of polyamines is another important function of this molecule. In this pathway, SAMe is decarboxylated by SAMe decarboxylase and its amino propyl group is transferred, first to putrescine and then to spermidine, to form polyamines.
Under normal conditions, this pathway does not account for>5% of the available SAMe, but this percentage is markedly increased under conditions of increased polyamine synthesis, as during liver regeneration. It is important to note that SAMe is also a regulator of enzyme activities and it coordinates the remethylation and transsulfuration pathways. SAMe acts as an allosteric inhibitor of methylene tetrahydrofolate reductase and as an activator of cystathionine-synthase. In this way, SAMe suppresses the synthesis of N-5-methyltetrahydrofolate, an important substrate required for remethylation reactions, and promotes the initial reaction of transsulfuration. Thus, the intracellular SAMe concentration is an important determinant of the fate of homocysteine, a risk factor for cardiovascular disease.
SAMe Role in Liver Diseases
Many of these nutrients, including methionine, must first be activated in the liver or in other tissues before they can exert their key functions. This activating process, however, is altered by liver disease and, as a consequence, nutritional requirements change. For instance, methionine has to be converted to S-adenosyl-l-methionine (SAMe) before it can act as the main cellular methyl donor.
This function of SAMe is important for the metabolism of nucleic acids and for the structure and function of membranes and many other cellular constituents. These are often disturbed in various liver diseases but cannot be restored by the simple administration of methionine. Indeed, experimentally, it has been shown that even a 7-fold increase in the normal dietary methionine content failed to significantly alter hepatic SAMe. This is exacerbated when there is significant liver disease, which is commonly associated with impairment of the enzyme activating methionine to SAMe. Therefore, supplementation with methionine is useless in most such circumstances and may even result in toxicity because of its accumulation as a result of non-utilization. Accordingly, one must bypass the enzyme deficiency due to liver disease and provide the product of the defective reaction, namely SAMe, which becomes crucial for the functioning of the cell under these pathologic conditions.
Thus, SAMe then becomes the essential nutrient instead of methionine. It is a typical example of a "conditional essential amino acid" and what is now also called a super nutrient, namely an activated nutrient that must be provided to meet the normal cellular requirements when its endogenous synthesis from a nutritional precursor becomes insufficient because of impairment in the activation process secondary to a pathologic state. Because the essential super nutrient SAMe is key to many basic cellular functions, it is not surprising that its lack is associated with many pathologic manifestations of liver diseases and that these can be corrected by simply providing the missing super nutrient.

Beneficial effects of SAMe on basic manifestations of liver disease

Role of SAMe on oxidative stress
Oxidative stress was shown to play a major pathogenic role in multiple disease states ranging from the hepatotoxicity of alcohol to the carcinogenicity of many compounds. The major natural defense mechanism against oxidative stress is reduced glutathione, which traps the excess of free radicals. Glutathione is a tripeptide, the rate-limiting amino acid being cysteine, and SAMe plays a fundamental role in the formation of cysteine.
Role of SAMe in transmethylation and transsulfuration reactions
Another basic cellular activity of SAMe is its role as a methyl donor and enzyme activator in the transmethylation and transsulfuration reactions key to membrane structure and function. For example, SAMe is essential for the transport processes and signal transmission across membranes. One of the important consequences of the failure of these functions is insufficiency of bile formation, a key aspect of many diseases of the liver, resulting in a pathologic state called cholestasis.
SAMe opposes successfully many of the cholestatic states. Given either orally or parenterally, SAMe improves both the pruritus and the biochemical indexes of cholestasis, such as serum bilirubin, alkaline phosphatise, and γ-glutamyltransferase.
In a multicenter, double-blind, placebo-controlled trial performed in 220 in-patients with chronic liver disease (chronic active hepatitis and cirrhosis, including primary biliary cirrhosis), serum markers of cholestasis and subjective symptoms (eg, pruritus and fatigue) significantly improved after SAMe treatment.
Cholestasis is not only an important manifestation of various liver disorders, but it also may complicate physiologic states such as pregnancy. SAMe was shown to be a useful therapy for cholestasis during pregnancy and for cholestasis that is sometimes associated with parenteral nutrition.
Role of SAMe in opposing fibrosis
The leading cause of morbidity and mortality in all major liver diseases is an inappropriately excessive healing process with uncontrolled scarring or fibrosis culminating in cirrhosis. Indeed, fibrosis can be viewed as an initially beneficial scarring process that has escaped control and results ultimately in cirrhosis.
SAMe was shown to be therapeutically useful in alleviating this process experimentally and for improving the outcome clinically.
The most common liver disease for which SAMe has been shown to be useful therapeutically is alcoholic liver injury, which includes all the pathologic manifestations, namely a deficiency in the activation of methionine to SAMe, in the pathogenic role of oxidative stress and glutathione deficiency, in complications of cholestasis, and in the devastating consequences of excessive liver fibrosis (leading to cirrhosis).
SAMe and the pathogenesis of alcoholic liver injury
Alcohol causes liver disease through a variety of pathogenic mechanisms. The major mechanisms include interactions with nutrition and toxic manifestations through generation of oxidative stress and production of the toxic metabolite acetaldehyde.
Interactions of alcohol with nutrition
In addition to its pharmacologic action, alcohol (ethanol) has considerable energy content (7.1 kcal/g). Thus, its consumption may cause primary malnutrition by displacing other nutrients in the diet because of the high energy content of the alcoholic beverages or because of associated socioeconomic and medical disorders. Secondary malnutrition may result from either maldigestion or malabsorption of nutrients caused by gastrointestinal complications associated with alcoholism. Alcohol also promotes nutrient degradation or impaired activation. Whereas it continues to be important to replenish nutritional deficiencies, it is crucial to recognize that, because of the alcohol-induced disease process, some nutritional requirements change.
Methionine and its utilization in liver diseases
In cirrhotic livers, a decrease in SAMe-synthetase activity is reported. As a consequence, methionine supplementation may be ineffective in alcoholic liver disease and SAMe depletion ensues, as was verified in nonhuman primates after long-term ethanol consumption. Additional factors that contribute to the decrease in hepatic SAMe are increased glutathione utilization secondary to enhanced free radical and acetaldehyde generation by the induced microsomal ethanol-oxidizing system.
Toxicity of acetaldehyde
Acetaldehyde, the product of all pathways of ethanol oxidation, is highly toxic and is rapidly metabolized to acetate, mainly by a mitochondrial aldehyde dehydrogenase, the activity of which is significantly reduced by chronic ethanol consumption. The decreased capacity of mitochondria in alcohol fed subjects to oxidize acetaldehyde, associated with unaltered or even enhanced rates of ethanol oxidation (and therefore acetaldehyde generation because of the induction of the microsomal ethanol-oxidizing system), results in an imbalance between the production and disposition of acetaldehyde. The latter causes the elevated acetaldehyde concentrations.
Acetaldehyde's toxicity is due, in part, to its capacity to form protein adducts, which results in antibody production, enzyme inactivation, and decreased DNA repair. Moreover, acetaldehyde promotes lipid peroxidation; one mechanism that promotes lipid peroxidation is glutathione depletion. The binding of acetaldehyde with cysteine, glutathione, or both may contribute to a decrease in liver glutathione.
Thus, acetaldehyde toxicity plays a fundamental role in alcohol-induced liver injury, and glutathione is a key defense mechanism by inactivating the free radicals generated by acetaldehyde and by binding to acetaldehyde itself. SAMe, in turn, serves as the main support for the maintenance of adequate glutathione concentrations.

Beneficial effects of SAMe in alcoholic liver disease

Membrane alterations are common in alcoholic liver injury and are also associated with a decrease in phosphatidylcholine, the backbone of the membranes. One pathway for the maintenance and preservation of adequate phosphatidylcholine concentrations in the liver membranes is the methylation of phosphatidylethanolamine to phosphatidylcholine through the action of SAMe. This vital function is impaired in alcoholic liver disease because, under these conditions, the activity of phosphatidylethanolamine methyltransferase is depressed.

Conclusion

Liver disorders, including alcoholic liver disease, are associated with and result in part from impaired activation of methionine to SAMe or from alcohol-induced oxidative stress, which results in the increased utilization of SAMe, a key precursor of cysteine-the rate-limiting amino acid of the tripeptide glutathione. Depletion of SAMe, the main methylating agent of the liver, and associated liver pathology can be corrected by the administration of this safe, yet therapeutically effective nutrient.
A significant therapeutic success in alcoholic liver disease was achieved in a recent long-term randomized, placebo-controlled, double-blind, multicenter clinical trial of SAMe in patients with alcoholic liver cirrhosis in whom SAMe improved survival or delayed liver transplantation.
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