In by Raphikammer


  • CSF, cerebrospinal fluid; GNMT, glycine N-methyltransferase;
  • GSH, glutathione; HCC, hepatocellular carcinoma;
  • Hcy, homocysteine; MAT, methionine adenosyltransferase;
  • MTA, 5-deoxy-5-methylthioadenosine; MTHFR,
  • 5,10-methylenetetrahydrofolate reductase; NASH, nonalcoholic
  • steatohepatitis; SAH, (S)-adenosylhomocysteine;
  • SAMe, (S)-adenosylmethionine.


Common and Scientific Name

S-Adenosyl-L-methionine, also known as 5-[(3-Amino-3-

carboxypropyl) methylsulfonium]-5-deoxyadenosine; (S)-

(5-deoxyadenosine-5-yl) methionine; [C15H23N6O5S]+, is

abbreviated in the scientific literature as AdoMet, SAM,

or SAMe. In the early literature, before the identification

of its structure, SAMe was known as “active methionine.”

General Description

SAMe was discovered in 1953 and since then has been

shown to regulate key cellular functions such as differentiation,

growth, and apoptosis. Abnormal SAMe content

has been linked to the development of experimental and

human liver disease, and this led to the examination of the

effect of SAMe supplementation in various animal models

of liver disease and in patients with liver disease. Both

serum and cerebrospinal fluid (CSF) levels of SAMe have

been reported to be low in depressed patients, which has

led to the examination of the effect of SAMe treatment

in this condition. The effect of SAMe in the treatment of

other diseases, such as osteoarthritis, has also been investigated.

This chapter reviews (i) the biochemistry and

functions of SAMe; (ii) altered SAMe metabolism in liver

disease; (iii) SAMe deficiency in depression; and (iv) the

effect of SAMe treatment in liver disease, depression, and



SAMe Discovery

Although SAMe was discovered by Giulio Cantoni in

1953, the story of this molecule begins in 1890 with

Wilhelm His when he fed pyridine to dogs and

isolated N-methylpyridine from the urine and emphasized

the need to demonstrate both the origin of the

methyl group as well as the mechanism for its addition

to the pyridine (1). Both questions were addressed

by Vincent du Vigneaud who, during the late 1930s,

demonstrated that the sulfur atom of methionine was

converted to cysteine through the “transsulfuration”

pathway and discovered the “transmethylation” pathway,

that is, the exchange of methyl groups between

methionine, choline, betaine, and creatine. In 1951, Cantoni

demonstrated that a liver homogenate supplemented

with ATP and methionine converted nicotinamide to N Methylnicotinamide.

Two years later, he established that

methionine and ATP reacted to form a product, that he

originally called “Active Methionine,” capable of transferring

its methyl group to nicotinamide, or guanidinoacetic

acid, to form N-methylmethionine, or creatine in the

absence of ATP, which, after determination of its structure,

he called “AdoMet” (Fig. 1). Subsequently, Cantoni

and his colleagues discovered the enzyme that synthesizes

SAMe, methionine adenosyltransferase (MAT);

(S)-adenosylhomocysteine (SAH), the product of transmethylation

reactions; and SAH hydrolase, the enzyme

that converts SAH into adenosine and homocysteine

(Hcy). At about the same time, Bennett discovered that

folate and vitamin B12 could replace choline as a source of

methyl groups in rats maintained on diets containing Hcy

in place of methionine, a finding that led to the discovery

of methionine synthase (MS). In 1961, Tabor demonstrated

that the propylamino moiety of SAMe is

converted via a series of enzymatic steps to spermidine

and spermine. In the biosynthesis of polyamines,

5-deoxy-5-methylthioadenosine (MTA) was identified

as an end product. Thus, by the beginning of the 1960s,

Laster’s group could finally provide an integrated view,

similar to that depicted in Figure 2, combining the

transmethylation and transsulfuration pathways with

polyamine synthesis.

Since then, SAMe has been shown to donate (i) its

methyl group to a large variety of acceptor molecules

including DNA, RNA, phospholipids, and proteins;

(ii) its sulfur atom, via a series of reactions, to cysteine and

glutathione (GSH), a major cellular antioxidant; (iii) its

propylamino group to polyamines, which are required

for cell growth; and (iv) its MTA moiety, via a complex

set of enzymatic reactions known as the “methionine salvage

pathway,” to the resynthesis of this amino acid. All

these reactions can affect a wide spectrum of biological

processes ranging from metal detoxification and catecholamine

metabolism to membrane fluidity, gene expression,

cell growth, differentiation, and apoptosis (2), to

establish what Cantoni called the “AdoMet Empire.”

SAMe Synthesis and Metabolism

MAT is an enzyme extremely well conserved through evolution

with 59% sequence homology between the human

and Escherichia coli isoenzymes. In mammals, there are:

AdoMeit,, SAM,, SAMee

Figure 1 Structure of SAMe. (S)-adenosylmethionine (SAMe) has been

shown to donate: (i) its methyl group to a large variety of acceptor molecules

including DNA, RNA, phospholipids, and proteins; (ii) its sulfur atom, via a

series of reactions, to cysteine and glutathione, a major cellular antioxidant;

(iii) its propylamino group to polyamines, which are required for cell growth;

and (iv) its MTA moiety, via a complex set of enzymatic reactions known as

the “methionine salvation pathway,” to the resynthesis of this amino acid.

  • MS
  • MTA
  • Putrescine Spermidine
  • Spermine
  • MTA
  • Met
  • SAMe
  • SAH
  • Hcy
  • Cys
  • CBS
  • MAT
  • MTs
  • Cystathionine
  • THF
  • 5,10-MTHF
  • 5-MTHF
  • XX-
  • CH3
  • Ser
  • α-Ketobutyrate
  • Betaine
  • N,N-Dimethyl-Gly
  • Serine
  • Glycine
  • GSH

into homocysteine (Hcy) via (S)-adenosylmethionine (SAMe) and (S)-

adenosylhomocysteine (SAH). The conversion of Met into SAMe is catalyzed

by methionine adenosyltransferase (MAT). After decarboxylation, SAMe can

donate the remaining propylamino moiety attached to its sulfonium ion to

putrescine to form spermidine and methylthioadenosine (MTA) and to spermidine

to form spermine and a second molecule of MTA. SAMe donates

its methyl group in a large variety of reactions catalyzed by dozens of

methyltransferases (MTs), the most abundant in the liver being glycine-N Methyltransferase

(GNMT). The SAH thus generated is hydrolyzed to form

Hcy and adenosine through a reversible reaction catalyzed by SAH hydrolase.

Hcy can be methylated to form methionine by two enzymes: methionine

synthase (MS) and betaine homocysteine methyltransferase (BHMT). In the

liver, Hcy can also undergo the transsulfuration pathway to form cysteine via

a two-step enzymatic process. In the presence of serine, Hcy is converted

to cystathionine in a reaction catalyzed by cystathionine -synthase (CBS).

Cystathionine is then hydrolyzed by cystathionase to form cysteine, a precursor

of the synthesis of glutathione (GSH). In tissues other than the liver,

kidney, and pancreas, cystathionine is not significantly converted to GSH due

to the lack of expression of one or more enzymes of the transsulfuration

pathway. The expression of BHMT is also limited to the liver. All mammalian

tissues convert Met into Hcy, via SAMe and SAH, and remethylate Hcy into

Met via the MS pathway. Abbreviations: THF, tetrahydrofolate; 5,10-MTHF,

methylenetetrahydrofolate; 5-MTHF, methyltetrahydrofolate; Ser, serine; Gly,

glycine; X, methyl acceptor molecule; X-CH3, methylated molecule.

three isoforms of MAT (MATI, MATII, and MATIII) that

are encoded by two genes (MAT1A and MAT2A). MATI

andMATIII are tetrameric and dimeric forms, respectively,

of the same subunit (1) encoded by MAT1A, whereas the

MATII isoform is a tetramer of a different subunit (2) encoded

by MAT2A. A third gene, MAT2β encodes for a

subunit that regulates the activity of MATII (lowering the

Km and Ki for methionine and SAMe, respectively) but not

ofMATI orMATIII (2). Adult differentiated liver expresses

MAT1A, whereas extrahepatic tissues and fetal liver express

MAT2A. MAT1A expression is silenced in HCC. It

is an intriguing question why there are three different

MAT isoforms in the liver. The predominant liver form,

MATIII, has lower affinity for its substrates, a hysteretic

response to methionine (a hysteretic behavior, defined as

a slow response to changes in substrate binding, has been

described for many important enzymes in metabolic regulation),

and higher Vmax, contrasting with the other two

enzymes. On the basis of the differential properties of hepatic

MAT isoforms, it has been postulated that MATIII is

the truly liver-specific isoform. Under normal conditions,

MATI would, as MATII outside the liver, synthesize most

of the SAMe required by the hepatic cells. However, after

an increase in methionine concentration, that is, after

a protein-rich meal, conversion to the high-activity

MATIII would occur and methionine excess will be eliminated

(Fig. 2). This will lead to accumulation of SAMe

and activation of glycine N-methyltransferase (GNMT),

the main enzyme involved in hepatic SAMe catabolism.

Consequently, the excess of SAMe will be eliminated and

converted to homocysteine via SAH. Once formed, the

excess of homocysteine will be used for the synthesis of

cysteine and -ketobutyrate as a result of its transsulfuration.

This pathway involves two enzymes: cystathionine

-synthase (CBS), that is activated by SAMe, and

cystathionase. Cysteine is then utilized for the synthesis

of GSH as well as other sulfur-containing molecules

such as taurine, while -ketobutyrate penetrates the mitochondria

where it is decarboxylated to carbon dioxide

and propionyl CoA. Because SAMe is an inhibitor of 5,10-

methylenetetrahydrofolate-reductase (MTHFR), this will

prevent the regeneration of methionine after a load of this

amino acid. At the mRNA level, SAMe maintains MAT1A

and GNMT expression while inhibiting MAT2A expression.

This modulation by SAMe of both the flux of methionine

into the transsulfuration pathway and the regeneration

of methionine maximizes the production of cysteine

and -ketobutyrate, and consequently of ATP, after a methionine

load minimizing the regeneration of this amino

acid (oxidative methionine metabolism).


Altered SAMe Metabolism in Liver Disease

Accumulating evidence supports the importance of maintaining

normal SAMe level in mammalian liver, as both

chronic deficiency and excess lead to liver injury, steatosis,

and development of hepatocellular carcinoma (HCC)

(2,3). Majority of the patients with cirrhosis have impaired

SAMe biosynthesis because of lower MAT1A mRNA levels

and inactivation of MATI/III (4,5). However, patients

with GNMT mutations have been identified and they also

S-Adenosylmethionine 3

have evidence of liver injury (6). In mice, loss of GNMT

results in supraphysiological levels of hepatic SAMe and

aberrant methylation (7). The molecular mechanisms responsible

for injury and HCC formation are different in

MAT1A and GNMT knockout mice but these findings illustrate

the importance of keeping SAMe level within a

certain range within the cell.

In contrast to normal non proliferating (differentiated)

hepatocytes, which rely primarily on MATI/III to

generate SAMe and maintain methionine homeostasis,

embryonic and proliferating adult hepatocytes as well

as liver cancer cells instead rely on MATII to synthesize

SAMe (2). Liver cancer cells often have very low

levels of GNMT and CBS expression and increased expression

of MAT2β, which, as mentioned earlier, lowers

the Km for methionine and the Ki for SAMe of MATII.

Consequently, proliferating hepatocytes and hepatoma

cells tend to utilize methionine into protein synthesis regardless

of whether methionine is present in high or low

amounts and to divert most homocysteine away from the

transsulfuration pathway by regenerating methionine and

tetrahydrofolate (THF) (aerobic methionine metabolism).

MAT2A/MAT2β-expressing hepatoma cells have lower

SAMe levels than cells expressing MAT1A, which also favors

the regeneration of methionine and THF. From these

results, it becomes evident that proliferating hepatocytes

and hepatoma cells do not tolerate well high SAMe levels

for converting methionine via the transsulfuration pathway

to cysteine and -ketobutyrate.

The finding that MAT1A, GNMT, MTHFR, and CBS

knockout mice spontaneously develop fatty liver (steatosis)

and, in the case of MAT1A- and GNMT-deficient animals,

HCC also (3) demonstrates the synchronization of

methionine metabolism with lipid metabolism and hepatocyte


The medical implications of these observations are

obvious, since the majority of cirrhotic patients, independent

of the etiology of their disease, have impaired

metabolism of methionine and reduced hepatic SAMe

synthesis and are predisposed to develop HCC (4,5); and

individuals with GNMT mutations that lead to abnormal

SAMe catabolism develop liver injury (6). Moreover, the

observation that genetic polymorphisms that associate

with reduced MTHFR activity and increased thymidylate

synthase activity, both of which are essential in minimizing

uracyl misincorporation into DNA, may protect

against the development of HCC in humans (8) further

supports that this synchronization may be an adaptive

mechanism that is programmed to fit the specific needs of

hepatocytes, and that alterations in the appropriate balance

between methionine metabolism and proliferation

may be at the origin of the association of cancer with fatty

liver disease.

An explanation for these observations connecting

methionine metabolism with the development of fatty

liver and HCC has remained elusive because the association

of SAMe with lipid metabolism and hepatocyte

proliferation is, at first glance, not intuitive. During

the past years, a signaling pathway that senses cellular

SAMe content and that involves AMP-activated protein

kinase (AMPK) has been identified to operate in hepatocytes

(9,10). AMPK is a serine/threonine protein kinase

that plays a crucial role in the regulation of energy homeostasis

and cell proliferation. AMPK is activated by stress

conditions leading to an increase in the AMP/ATP ratio,

such as during liver regeneration. Once activated, AMPK

shuts down anabolic pathways that mediate the synthesis

of proteins, fatty acids, lipids, cholesterol, and glycogen

and stimulates catabolic pathways such as lipid oxidation

and glucose uptake restoring ATP levels and keeping

the cellular energy balance. The finding that in the

liver AMPK activity is tightly regulated by SAMe (9,10)

has provided a first link between methionine metabolism,

lipid metabolism, and cell proliferation. Moreover, excess

SAMe can induce aberrant methylation of DNA and

histones, resulting in epigenetic modulation of critical

carcinogenic pathways (7). Finally, there is evidence indicating

that SAMe regulates proteolysis, widening its

spectrum of action. In hepatocytes, the protein levels of

prohibitin 1 (PHB1) (11), the apurinic/apyrimidininc endonuclease

(APEX1) (12), and the dual specificity MAPK

phosphatase (DUSP1) (13) are stabilized by SAMethrough

a process that may involve proteasome inactivation. PHB1

is a chaperone-like protein involved in mitochondrial

function, APEX1 is a key protein involved in DNA repair

and genome stability, and DUSP1 is a member of a family

of mitogen-activated protein kinases (MAPKs) phosphatases,

which simultaneously dephosphorylates both

serine/threonine and tyrosine residues.

SAMe Deficiency in Depression

Major depression has been associated with a deficiency

in methyl groups (folate, vitamin B12, and SAMe) (14,15).

Thus, depressed patients often have low plasma folate and

vitamin B12 and reduced SAMe content in the CSF. Moreover,

patients with low plasma folate appear to respond

less well to antidepressants. The mechanism by which low

SAMe concentrations may contribute to the appearance

and evolution of depression is, however, not well known.

SAMe-dependent methylation reactions are involved in

the synthesis and inactivation of neurotransmitters, such

as noradrenaline, adrenaline, dopamine, serotonin, and

histamine; and the administration of drugs that stimulate

dopamine synthesis, such as L-dihydroxyphenylalanine,

cause a marked decrease in SAMe concentration in rat

brain and in plasma and CSF in humans. Moreover, various

drugs that interfere with monoaminergic neurotransmission,

such as imipramine and desipramine, reduce

brain SAMe content in mice (14,15). As in the liver, abnormal

SAMe levels may contribute to depression through

perturbation of multiple metabolic pathways in the brain.

Interestingly, alterations in methionine metabolism that

lead to a decrease in the brain SAMe/SAH ratio associate

with reduced leucine carboxyl methyltransferase-1

(LCMT-1) and phosphoprotein phosphatase 2AB (PP2AB)

subunit expression, and accumulation of unmethylated

PP2A (16). PP2A enzymes exist as heterotrimeric complexes

consisting of catalytic (PP2AC), structural (PP2AA),

and regulatory (PP2AB) subunits (17). Different PP2AB

subunits have been described that determine the substrate

specificity of the enzyme. PP2AC subunit is methylated

by SAMe-dependent LCMT-1 and demethylated by a specific

phosphoprotein phosphatase methylesterase (PME1).

PP2AC methylation has no effect on PP2A activity but has

a crucial role in the recruitment of specific PP2AB subunits

4 Mato and Lu

to the PP2AA,B complex and therefore PP2A substrate

specificity. Downregulation of LCMT-1 and PP2AB and

accumulation of unmethylated PP2A are associated with

enhanced Tau phosphorylation and neuronal cell death



SAMe Treatment in Animal Models of Liver Disease

The importance of the metabolism of methyl groups in

general, and SAMe in particular, to normal hepatic physiology,

coupled with the convincing body of evidence

linking abnormal SAMe content with the developmental

of experimental and human liver disease, led to the

examination of the effect of SAMe supplementation in

various animal models of liver disease. SAMe administration

to alcohol-fed rats and baboons reduced GSH depletion

and liver damage (2,18). SAMe improved survival

in animal models of galactosamine-, acetaminophen- and

thioacetamide-induced hepatotoxicity, and in ischemia reperfusion–

induced liver injury (18). SAMe treatment

also diminished liver fibrosis in rats treated with carbon

tetrachloride (18) and reduced neoplastic hepatic nodules

in animal models of HCC (19,20). Similar to the liver,

SAMe can block mitogen-induced growth and induce

apoptosis in human colon cancer cells (21,22).

SAMe Treatment in Human Diseases

SAMe has been used in humans for the past 20 years for the

treatment of osteoarthritis, depression, and liver disease.

In 2002, the Agency for Healthcare Research and Quality

(AHRQ) reviewed 102 individual clinical trials of SAMe

(23). Of these 102 studies, 47 focused on depression, 14

focused on osteoarthritis, and 41 focused on liver disease.

Of the 41 studies in liver disease, 9 were for cholestasis of

pregnancy, 12 were for other causes of cholestasis, 7 were

for cirrhosis, 8 were for chronic hepatitis, and 4 were for

various other chronic liver diseases.

Pharmacokinetics of SAMe

Orally administered SAMe has low bioavailability, presumably

because of a significant first-pass effect (degradation

in the gastrointestinal tract) and rapid hepatic

metabolism. Peak plasma concentrations obtained with

an enteric-coated tablet formulation are dose related, with

peak plasma concentrations of 0.5 to 1 mg/L achieved

three to five hours after single doses ranging from 400 to

1000 mg (23). Peak levels decline to baseline within 24

hours. One study showed a significant gender difference

in bioavailability, with women showing three- to sixfold

greater peak plasma values than men (23). Plasma-protein

binding of SAMe is no more than 5%. SAMe crosses the

blood–brain barrier, with slow accumulation in the CSF.

Unmetabolized SAMe is excreted in urine and feces.

Parenterally administered SAMe has much higher

bioavailability. However, this form is currently not approved

for use in the United States.

SAMe Treatment in Liver Diseases

Out of the 41 studies in liver disease analyzed by AHRQ,

8 studies were included in a meta-analysis of the efficacy

of SAMe to relieve pruritus and decrease elevated

serum bilirubin levels associated with cholestasis of pregnancy

(23). Compared with placebo, treatment with SAMe

was associated with a significant decrease in pruritus and

serum bilirubin levels. Similar results were obtained when

six studies were included in a meta-analysis of the efficacy

of SAMe to relieve pruritus and decrease bilirubin levels

associated with cholestasis caused by various liver diseases

other than pregnancy.

In 2001, the Cochrane Hepato-Biliary Group analyzed

eight clinical trials of SAMe treatment of alcoholic

liver disease including 330 patients (24). This meta analysis

found SAMe decreased total mortality [odds

ratio (OR) 0.53, 95% confidence interval (CI): 0.22 to 1.29]

and liver-related mortality (OR 0.63, 95% CI: 0.25 to 1.58).

However, because many of the studies were small and

the quality of the studies varied greatly, the Cochrane

Group concluded, “SAMe should not be used for alcoholic

liver disease outside randomized clinical trials” (24). The

AHRQ reached a similar conclusion, “For liver conditions

other than cholestasis additional smaller trials should be

conducted to ascertain which patient populations would

benefit more from SAMe, and what interventions (dose

and route of administration) are most effective” (23). The

Cochrane Hepato-Biliary Group also concluded that only

one trial including 123 patients with alcoholic cirrhosis

used adequate methodology and reported clearly on mortality

and liver transplantation. In this study (25), mortality

decreased from 30% in the placebo group to 16% in

the SAMe group (P = 0.077). When patients with more

advanced cirrhosis (Child score C) were excluded from

the analysis (eight patients), the mortality was significantly

less in the SAMe group (12%) as compared with the

placebo group (25%, P=0.025). In this study, 1200 mg/day

was administered orally. Unfortunately, new controlled

prospective double-blind multicenter studies on the benefits

of SAMe for liver diseases are lacking.


SAMe Treatment in Depression

Out of the 39 studies in depression analyzed by the AHRQ,

28 studies were included in a meta-analysis of the efficacy

of SAMe to decrease symptoms of depression (23). Compared

with placebo, treatment with SAMe was associated

with an improvement of approximately six points in the

score of the Hamilton Rating Scale for Depression measured

at three weeks (95% CI: 2.2 to 9.0). This degree of

improvement was statistically as well as clinically significant.

However, compared with the treatment with conventional

antidepressant pharmacology, treatment with

SAMe was not associated with a statistically significant

difference in outcomes. With respect to depression, the

AHRQ report concluded, “Good dose-escalation studies

have not been performed using the oral formulation of

SAMe for depression” (23). The AHRQ report also concluded,

that “Additional smaller clinical trials of an exploratory

nature should be conducted to investigate uses

of SAMe to decrease the latency of effectiveness of conventional

antidepressants and to treat of postpartum depression”

(23). Unfortunately, these clinical studies are still


SAMe Treatment in Osteoarthritis

Out of the 13 studies in osteoarthritis analyzed by the

AHRQ, 10 studies were included in a meta-analysis of

S-Adenosylmethionine 5

the efficacy of SAMe to decrease pain of osteoarthritis

(23). Compared with placebo, one large randomized clinical

trial showed a decrease in the pain of osteoarthritis

with SAMe treatment. Compared with the treatment

with nonsteroidal anti-inflammatory medications, treatment

with oral SAMe was associated with fewer adverse

effects while comparable in reducing pain and improving

functional limitation. In 2009, the Cochrane Osteoarthritis

Group analyzed 4 clinical trials including 656 patients, all

comparing SAMe with placebo (26). The Cochrane Group

concluded, “The effects of SAMe on both pain and function

may be potentially clinically relevant and, although

effects are expected to be small, deserve further clinical

evaluation in adequately sized randomized, parallel group

trials in patients with knee or hip osteoarthritis.

Meanwhile, routine use of SAMe should not be

advised” (26).

Adverse Effects

The risks of SAMe are minimal. SAMe has been used in

Europe for more than 20 years and is available under prescription

in Italy, Germany, United Kingdom, and Canada,

and over the counter as a dietary supplement in the United

States, China, Russia, and India. The most common side

effects of SAMe are nausea and gastrointestinal disturbance,

which occurs in less than 15% of treated subjects.

Recently, SAMe administration to mice treated with cisplatin

has been found to increase renal dysfunction (27).

Whether SAMe increases cisplatin renal toxicity in humans

is not known.

Interactions with Herbs, Supplements, and Drugs

Theoretically,SAMe might increase the effects and adverse

effects of products that increase serotonin levels, which

include herbs and supplements such as Hawaiian Baby

Woodrose, St. John’s wort, and L-tryptophan, as well as

drugs that have serotonergic effects. These drugs include

tramadol (Ultram), pentazocine (Talwin), clomipramine

(Anafranil), fluoxetine (Prozac), paroxetine (Paxil), sertraline

(Zoloft), amitriptyline (Elavil), and many others. It is

also recommended that SAMe should be avoided in patients

taking monoamine oxidase inhibitors or within two

weeks of discontinuing such a medication.


Although evidence linking abnormal SAMe content with

the development of experimental and human liver disease

is very convincing, the results of clinical trials of

SAMe treatment of liver disease are not conclusive. Consequently,

SAMe should not be used outside clinical trials

for the treatment of liver conditions other than cholestasis.

A new clinical study enrolling a larger number of patients

should be carried out to confirm that SAMe decreases

mortality in alcoholic liver cirrhosis. This is important because

if SAMe improves survival, SAMe will become the

only available treatment for patients with alcoholic liver


Although depression has been associated with a deficiency

in SAMe, it is not yet clear whether this is a consequence

or the cause of depression. To clarify this point,

more basic research and the development of new experimental

models are needed. Clinical trials indicate that

SAMe treatment is associated with an improvement of

depression. Dose studies using oral SAMe should be performed

to determine the best dose to be used in depression.

New studies should also be carried out where the

efficacy of SAMe is compared with that of conventional


With respect to osteoarthritis, at present there is no

evidence associating a deficiency in SAMe with the appearance

of the disease. Moreover, the efficacy of SAMe

in the treatment of osteoarthritis is also not convincing at present.



This work was supported by grants from NIH DK51719

(to S. C. L.) and AT-1576 (to S. C. L. and J. M. M.) and

SAF 2008-04800 (to J. M. M.). CIBERehd is funded by the

Instituto de Salud Carlos III.


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