S-Adenosyl-L-Methionine

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Abstract
S-Adenosyl-L-methionine (SAMe) is a naturally occurring molecule distributed to virtually all body tissues and fluids. It is of fundamental importance in a number of biochemical reactions involving enzymatic transmethylation, contributing to the synthesis, activation and/or metabolism of such compounds as hormones, neurotransmitters, nucleic acids, proteins, phospholipids and certain drugs. The administration of a stable salt of SAMe, either orally or parenterally, has been shown to restore normal hepatic function in the presence of various chronic liver diseases (including alcoholic and non-alcoholic cirrhosis, oestrogen-induced and other forms of cholestasis), to prevent or reverse hepatotoxicity due to several drugs and chemicals such as alcohol, paracetamol (acetaminophen), steroids and lead, and to have antidepressant properties. In all of these studies SAMe has been very well tolerated, a finding of great potential benefit given the well-known adverse effects of tricyclic antidepressants with which it has been compared in a few trials. Thus, with its novel mechanisms of action and good tolerability, SAMe is an interesting new therapeutic agent in several diverse disease conditions, but its relative value remains to be determined in appropriate comparisons with other treatment modalities in current use. S-Adenosyl-L-methionine (commonly known as SAMe) acts as a methyl group donor in many transmethylation reactions, including those involved with the biosynthesis of phospholipids which play several important roles within the cell membrane. These roles include regulation of cellular enzymatic and bioelectrical activity and the maintenance of membrane fluidity. Loss of the latter in brain cells of aged animals has been linked with loss of dopaminergic and β-adrenergic binding sites and changes in cell membrane composition. The exogenous administration of SAMe maintains normal phospholipid ratios and restores enzymatic activity leading to normalisation of metabolic processes within the cell. This may explain, at least in part, the effect of SAMe in normalising several indices of hepatic function which are altered in chronic liver disease where changes in cell membrane composition and enzymatic activity of hepatocytes have been demonstrated. Activation of enzymes which affect the synthesis and metabolism of neurotransmitters may also be related to maintenance of normal cell membrane function and may explain the effects of SAMe on mood in patients with affective disorders. Release of methyl groups from the SAMe molecule results in activation of the transsulphuration pathway leading to the formation of glutathione, the main cellular antioxidant responsible for the detoxification of various compounds, including lead and paracetamol. Thus, regulation of the transsulphuration pathway is an important effect and one which may be responsible for its beneficial action on drug-and chemical-induced liver disease. The almost universal distribution of SAMe in body tissues and its complex role in metabolic processes, all of which depend in some way on methylation reactions, complicate the complete characterisation of its effects on cellular biochemistry. As a result the mechanism of its actions in various diverse disease states remains speculative. The role of SAMe in transmethylation reactions and as a precursor of sulphur-containing compounds via the transsulphuration pathway is fundamentally important in the liver, as both pathways have been shown to be abnormal in the presence of liver disease. In the presence of cirrhosis, methionine metabolism is decreased, and the activities of S-adenosyl-methionine synthetase and phospholipid methyltransferase are reduced, possibly leading to lessened production of sulphated compounds and phosphatidylcholine. Levels of the important thiol compounds glutathione and cysteine are reduced in plasma. Various animal models have been used to demonstrate the protective effect of SAMe against intrahepatic cholestasis induced by a range of compounds, including oestrogen. The mechanism of action of SAMe in oestrogen-induced cholestasis appears to be via increased enzyme activity and fluidity of liver plasma membranes, and maintenance of phospholipid activity in bile salt transport systems. Preliminary findings of a preventative effect of SAMe in women with oestrogen-induced cholestasis have been augmented by results of small therapeutic trials (see below). Acute toxicity studies in animals reveal that SAMe can prevent mortality induced by paracetamol (acetaminophen) and acute and chronic lead poisoning. Some success has been achieved with the use of SAMe in treating patients with lead poisoning (see below). Maintenance of glutathione stores is instrumental in the prevention by SAMe of hepatotoxicity due to these agents. SAMe administered to rats and baboons subjected to chronic ethanol ingestion has been shown to maintain or prevent depletion of glutathione levels, to normalise mitochondrial enzyme activity, and to prevent production of acetaldehyde and deposition of fat in the liver. In healthy volunteers, plasma concentrations of ethanol and acetaldehyde were significantly lower when SAMe was ingested concomitantly with ethanol. SAMe has been shown in animals and humans to be distributed to the brain where it stimulates the activity of dopaminergic and serotonergic pathways, probably through its involvement in transmethylation processes. Levels of SAMe, and of 5-hydroxy indoleacetic acid (5HIAA) and homovanillic acid, increase in the cerebrospinal fluid of humans after administration of SAMe. The interplay of folate and SAMe pathways in influencing mood is a topic of considerable study, with recent work linking red cell folate levels to levels of 5HIAA in cerebrospinal fluid. Reductions in S-adenosyl-methionine syntlietase and phosphatidylcholine in erythrocytes of depressed patients suggest a disruption of SAMe-dependent pathways, and form the basis for the use of SAMe in depressed patients (see below). SAMe has been shown invitroto enhance ATP levels in erythrocytes, enabling restoration of cell shape and conservation of deformability. Invivo, blood viscosity was reduced following injection of SAMe. Limited trials in healthy volunteers have demonstrated very low bioavailability after oral administration of SAMe, indicative of a significant first-pass effect and rapid metabolism in the liver. Peak plasma concentrations obtained with an enteric-coated tablet formulation are dose related, with a peak plasma concentration of 0.5 to 1 mg/L achieved 3 to 5 hours after single doses in the range of 400 to 1000mg. Single intravenous doses of SAMe (100 and 500mg) have yielded volumes of distribution of 0.41 and 0.44 L/kg, respectively. Plasma protein binding is 5% or less. The rate of distribution to all body tissues is related to their degree of vascularity and blood flow. SAMe crosses the blood-brain barrier, with slow accumulation in the cerebrospinal fluid. Animal data suggest that exogenously administered SAMe follows the same metabolic pathways as the endogenous compound, namely, transmethylation, transsulphuration and decarboxylation. By 24 hours after intravenous administration of SAMe 100 or 500mg in healthy volunteers, 34% and 40% of unchanged drug, respectively, had appeared in urine. Urinary excretion of an oral 200mg dose of SAMe has been reported as 15.5% in 48 hours with faeces containing 23.5% at 72 hours. The remainder was probably incorporated into stable cellular pools. The half-life of SAMe in healthy volunteers was 80 to 100 minutes and 121 ininutes in a small group of patients with chronic liver disease. Trials in small numbers of patients with various types of chronic liver disease, including biliary or alcoholic cirrhosis, hepatitis or drug-induced cholestasis, have confirmed the short term effect of SAMe (intravenously or orally) relative to placebo in normalising measures of liver function (e.g. plasma levels of aspartate aminotransferase, γ-glutamyl transpeptidase, alkaline phosphatase, cysteine, taurine and methionine). Patients with chronic lead poisoning have shown reversal of liver enzyme abnormalities after SAMe therapy. Moreover, severe pruritus has been ameliorated in patients with cholestasis of diverse aetiology. Of interest is the apparent ability of SAMe, when given concomitantly, to protect against hepatic dysfunction caused by other drugs, including steroids, certain anticon-vulsants, and tricyclic antidepressants, paracetamol and alcohol. SAMe was effective in normalising biochemical parameters in small groups of patients with metabolic disorders of bilirubin and porphyrin metabolism, such as Gilbert’s syndrome and infantile porphyria cutanea tarda. The major effect of SAMe in depressed patients is elevation of mood, the precise mechanism of which is unknown. Non-comparative trials in small groups of patients with various types of depression have shown a consistent improvement in mood with SAMe in daily dosages up to 1600mg orally or 500mg parenterally for up to 6 weeks, as determined by the Hamilton rating scale, with those patients recently diagnosed or previously responding to antidepressants being most improved. In a number of short term randomised, double-blind trials SAMe 75 to 400mg administered parenterally was consistently superior to placebo and was at least as effective as other antidepressant drugs administered parenterally (nomifensine, amitriptyline, imipramine and clomipramine), generally having an onset of action within the first 2 weeks of treatment. Furthermore, in combination with another agent (the β2-agonist fenoterol, mianserin or clomipramine), SAMe shortened the latency period and improved the response as compared with the other drug alone. The use of SAMe as an adjunct to treatment with other antidepressants is worthy of study if the time to treatment response can be reduced, especially in suicidal patients. Furthermore SAMe treatment was well tolerated, an asset in patients who experience significant adverse effects from tricyclic antidepressant therapy. The relative efficacy of SAMe administered orally should be pursued in longer term trials. The wide range of effects of SAMe administration has led to the investigation of its use in many diverse conditions. Isolated reports have included clinical trials involving patients with Alzheimer’s; disease and epilepsy, where its effect was predominantly on mood but no change in the underlying condition could be demonstrated; migraine, where the incidence and severity of attacks was reduced; and primary fibromyalgia, where both joint pain and associated depression were improved. However, none of the above effects of SAMe have been adequately studied in well-designed trials s’uch that any conclusions can be drawn regarding its possible efficacy. SAMe is very well tolerated. At oral doses of up to 1600mg daily no adverse effects have been noted other than occasional mild gastrointestinal effects. In a study of 20,641 patients with osteoarthritis the tolerability was assessed as good to very good in 87% of patients, the withdrawal rate being 5.2%, primarily early in treatment when doses were highest. In depressed patients tolerability was also good, with only a few patients developing anxiety. However, the transition from depression to hypomania was noted in some patients with bipolar illness. The recommended daily dose of SAMe for the treatment of liver disorders, such as cholestasis, is 800mg parenterally or 1600mg orally. For parenteral administration in depressive illness 200 to 400 mg/day should be given for 15 to 20 days. Oral therapy is in the dose range 400 to 1600 mg/day.

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