SAMe (S-ADENOSYLMETHIONINE) ABSTRACTS

(REFERENCE 1 OF 29)

The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders

Bottiglieri T; Hyland K; Reynolds EH Metabolic Disease Center, Baylor Research Institute, Dallas, Texas

Drugs, Aug 1994, 48 (2) p137-52,

This review focuses on the biochemical and clinical aspects of methylation in neuropsychiatric disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numerous transmethylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAMe is intimately linked with folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, myelopathy and peripheral neuropathy. SAMe has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems. SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-1 (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders. (115 Refs.)

(REFERENCE 2 OF 29)

Review article: S-adenosyl-L-methionine-a new therapeutic agent in liver disease?

Osman E; Owen JS; Burroughs AK University Dept of Medicine, Royal Free Hospital, UK

Aliment Pharmacol Ther, Feb 1993, 7 (1) p21-8,

The established biochemical effects of exogenous S-Adenosyl-L-Methionine (SAMe) are diverse and are still being explored in liver disease. Putative therapeutic effects could be exerted via different mechanisms. The established deficiency of SAMe synthetase in cirrhosis could by bypassed by exogenous SAMe, leading to increased levels of sulphur-containing amino acids and glutathione which would protect against oxidant stress and drug-induced hepatotoxicity (for example, paracetamol). Furthermore SAMe could act by improving membrane fluidity, and thus potentially improve or restore the function of receptors, enzymes and transporters in the cell surface. Membrane fluidity is known to be affected by alterations in cell membrane lipid composition in chronic liver disease. Very few therapeutic agents are effective for the symptomatic or specific treatment of chronic liver disease. SAMe has established biochemical and biophysical effects which in pilot studies ameliorate symptoms and biochemical parameters of cholestasis. Moreover, abnormalities in liver function tests (including transaminase values) also improve. Before SAMe can be considered as an established therapy for patients with hepatic disease, long-term controlled clinical trials of SAMe are needed to assess the benefit for patients' symptoms, well being, histological changes and progression of liver disease. (54 Refs.)

(REFERENCE 3 OF 29)

S-Adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha.

Watson WH, Zhao Y, Chawla RK Department of Internal Medicine, University of Kentucky Medical Center, Lexington, KY, U.S.A.

Biochem J 1999 Aug 15;342(Pt 1):21-25

Intracellular deficiency of S-adenosylmethionine (AdoMet) and elevated serum concentrations of tumour necrosis factor alpha (TNF) are hallmarks of toxin-induced liver injury. In these models, the administration of either exogenous AdoMet or antibody/soluble receptor for TNF attenuates the injury. We have demonstrated previously that the administration of exogenous AdoMet to AdoMet-deficient rats attenuated lipopolysaccharide (LPS)-induced liver injury and serum TNF concentrations. Here we report that AdoMet lowered the amount of TNF secreted by LPS-stimulated murine macrophage cells (RAW 264.7) in a dose-dependent manner. The inhibition of TNF release was correlated with changes in the steady-state TNF mRNA concentrations. Changes in TNF mRNA were not due to its altered stability and might have been due to an attenuation of the transcription rate of the TNF gene. The inhibition of TNF release in RAW cells was not mediated by GSH because treatment with AdoMet did not increase intracellular GSH. In addition, N-acetylcysteine, whereas it did increase GSH concentration, had no effect on LPS-stimulated TNF release in these cells. Exogenous AdoMet also attenuated LPS-induced serum TNF levels in normal rats sensitized with lead. Thus AdoMet administration might exert its hepatoprotective effects at least in part by its inhibitory effect on expression of the gene for TNF.

(REFERENCE 4 OF 29)

SAMe And Osteoarthritis

Gutierrez S; Palacios I; Sanchez-Pernaute O; Hernandez P; Moreno J; Egido J; Herrero-Beaumont G Research Laboratory, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.

Br J Rheumatol, Jan 1997, 36 (1) p27-31

S-Adenosyl-L-methionine (SAMe) is a naturally occurring compound involved in transmethylation and trans-sulphuration reactions. The administration of SAMe to patients with osteoarthritis seems to have a protective effect, although the mechanisms of its action are largely unknown. We have studied the effect of SAMe as a protective agent against the modifications induced by tumour necrosis factor alpha (TNF alpha) on synovial cell proliferation and extracellular matrix protein synthesis, two important hallmarks of progressive articular diseases. The stimulation of cells with 100 U/ml TNF alpha for 24 hours decreased the proliferative rate (58 +/- 14% with TNF alpha vs. basal 100%, P < 0.05), fibronectin (FN) mRNA expression (36 +/- 14% vs. basal, P < 0.05) and FN synthesis (79 +/- 20% vs basal, P > 0.05). By contrast, TNF alpha raised total protein and proteoglycan synthesis (127 +/- 12% vs basal and 239 +/- 40% vs. basal, respectively, P < 0.05). The addition of increasing concentrations of SAMe (10(-10)-10(-6) M) to synoviocytes incubated with TNF alpha reversed the effects induced by the cytokine, while SAMe alone did not modify significantly the metabolic processes studied. These results indicate that, in cultured synovial cells, SAMe restores basal conditions after cell damage elicited by TNF alpha stimulation.

(REFERENCE 5 OF 29)

Clinical Studies: SAME And Osteoarthritis

Di Padova C Clinical Research Department, BioResearch S.p.A., Liscate-Milan, Italy.

Am J Med, Nov 20 1987, 83 (5A) p60-5

Experimental investigations suggest that the administration of SAMe exerts analgesic and antiphlogistic activities and stimulates the synthesis of proteoglycans by articular chondrocytes with minimal or absent side effects on the gastrointestinal tract and other organs. The results of extensive clinical trials, which have enrolled about 22,000 patients with osteoarthritis in the last five years, support the clinical effectiveness and the optimal tolerability of SAMe administration. The intensity of therapeutic activity of SAMe against osteoarthritis is similar to that exerted by nonsteroidal anti-inflammatory drugs, but its tolerability is higher. Based on these findings, SAMe is proposed as the prototype of a new class of safe drugs for the treatment of osteoarthritis.

(REFERENCE 6 OF 29)

SAMe Impact on Hips And Knees

Glorioso S; Todesco S; Mazzi A; Marcolongo R; Giordano M; Colombo B; Cherie-Ligniere G; Mattara L; Leardini G; Passeri M; et al.

Int J Clin Pharmacol Res,1985, 5 (1) p39-49

A randomized double-blind multicenter clinical trial was carried out to verify the effectiveness and tolerance of S-adenosylmethionine (SAMe) vs. ibuprofen in 150 patients with hip and/or knee osteoarthritis. Both drugs were given orally, 400 mg thrice daily for 30 days. SAMe exhibited a slightly more marked activity than the reference drug in the management of the various painful manifestations of the joint disease. Minor side-effects developed in five patients of the SAMe group, and in 16 patients of ibuprofen group. No drop-outs occurred. No changes were observed in the routine laboratory tests.

(REFERENCE 7 OF 29)

SAMe Vs. Ibuprofen

A Muller-Fassbender H Rheumazentrum Bad Abbach, II Medizinische Klinik, Bad Abbach, Federal Republic of Germany.

Am J Med, Nov 20 1987, 83 (5A) p81-3

Thirty-six subjects with osteoarthritis of the knee, the hip, and/or the spine were enrolled in a randomized double-blind study. Patients received a daily oral dose of 1,200 mg of S-adenosylmethionine (SAMe) or 1,200 mg of ibuprofen for four weeks. Morning stiffness, pain at rest, pain on motion, crepitus, swelling, and limitation of motion of the affected joints were assessed before and after treatment. The total score obtained by the evaluation of all the individual clinical parameters improved to the same extent in patients treated with SAMe or ibuprofen. Both treatments were well tolerated and no patient from either group withdrew from the study.

(REFERENCE 8 OF 29)

Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial

Kagan BL; Sultzer DL; Rosenlicht N; Gerner RH Department of Psychiatry, West Los Angeles VA Medical Center, CA

Am J Psychiatry, May 1990, 147 (5) p591-5,

Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trial for 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patient with no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.

(REFERENCE 9 OF 29)

Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine

Bottiglieri T; Godfrey P; Flynn T; Carney MW; Toone BK; Department of Neurology, King's College Hospital, London UK

J Neurol Neurosurg Psychiatry, Dec 1990, 53 (12) p1096-8,

Cerebrospinal fluid (CSF) S-adenosylmethionine (SAM) levels were significantly lower in severely depressed patients than in a neurological control group. The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM, indicating that it crosses the blood-brain barrier in humans. These observations provide a rational basis for the antidepressant effect of SAM, which has been confirmed in several countries. CSF SAM levels were low in a group of patients with Alzheimer's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment.

(REFERENCE 10 OF 29)

S-adenosylmethionine blood levels in major depression: changes with drug treatment

Bell KM; Potkin SG; Carreon D; Plon L University of California, Irvine Medical Center, Orange 92668

Acta Neurol Scand Suppl, 1994, 154 p15-8,

INTRODUCTION-The relationship between plasma levels of S-adenosylmethionine (SAMe), an endogenous methyl donor, and clinical response were studied in patients with a DSM-III-R diagnosis of major depression. MATERIAL AND METHODS-A double-blind randomized protocol comparing oral SAMe with oral desipramine, involving a total of 26 patients, was employed. RESULTS-At the end of the 4-week trial, 62% of the patients treated with SAMe and 50% of the patients treated with desipramine had significantly improved. Regardless of the type of treatment, patients with a 50% decrease in their Hamilton Depression Scale (HAM-D) score showed a significant increase in plasma SAMe concentration. CONCLUSION-The significant correlation between plasma SAMe levels and the degree of clinical improvement in depressed patients regardless of the type of treatment suggests that SAMe may play an important role in regulating mood.

(REFERENCE 11 OF 29)

S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies

Bressa GM Department of Psychiatry, University Cattolica Sacro Cuore School of Medicine, Rome, Italy

Acta Neurol Scand Suppl, 1994, 154 p7-14,

INTRODUCTION-S-adenosyl-l-methionine (SAMe) is a naturally-occurring substance which is a major source of methyl groups in the brain. MATERIAL AND METHODS-We conducted a meta-analysis of the studies on SAMe to assess the efficacy of this compound in the treatment of depression compared with placebo and standard tricyclic antidepressants. RESULTS-Our meta-analysis showed a greater response rate with SAMe when compared with placebo, with a global effect size ranging from 17% to 38% depending on the definition of response, and an antidepressant effect comparable with that of standard tricyclic antidepressants. CONCLUSION-The efficacy of SAMe in treating depressive syndromes and disorders is superior with that of placebo and comparable to that of standard tricyclic antidepressants. Since SAMe is a naturally occurring compound with relatively few side-effects, it is a potentially important treatment for depression.

(REFERENCE 12 OF 29)

Nyctohemeral rhythm in the levels of S-adenosylmethionine in the rat pineal gland and its relationship to melatonin biosynthesis

Sitaram BR; Sitaram M; Traut M; Chapman CB School of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia

J Neurochem, Oct 1995, 65 (4) p1887-94,

Liquid chromatographic techniques that permit the simultaneous analysis of S-adenosylmethionine, melatonin, and its intermediary metabolites N-acetyl-5-hydroxytryptamine and 5-hydroxytryptamine within individual pineal glands have been developed. S-Adenosylmethionine has been shown to undergo a marked nyctohemeral rhythm in the pineal gland of the rat, with maximal levels occurring during the light period and minimal levels during the dark period. Detailed studies of the temporal relationships between the levels of S-adenosylmethionine and those of melatonin and its intermediary metabolites suggest that an association exists between the levels of S-adenosylmethionine and the status of the biosynthesis of melatonin. Exposure of animals to continuous light and the administration of the beta-adrenoreceptor antagonist propranolol were both found to inhibit the induction of melatonin synthesis and prevent the reduction in the levels of S-adenosylmethionine during the dark period. As a corollary the induction of melatonin biosynthesis following the administration of the beta-adrenoreceptor agonist isoproterenol during the light period was accompanied by a marked decrease in the levels of S-adenosylmethionine in the pineal gland. The significance of the link between the nyctohemeral rhythms in the levels of S-adenosylmethionine and the biosynthesis of melatonin in the pineal gland is discussed in the context of the therapeutic efficacy of S-adenosylmethionine as an antidepressant.

(REFERENCE 13 OF 29)

The antidepressant potential of oral S-adenosyl-l-methionine

Rosenbaum JF; Fava M; Falk WE; Pollack MH; Cohen LS; Cohen BM; Zubenko GS Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114

Acta Psychiatr Scand, May 1990, 81 (5) p432-6,

S-adenosyl-l-methionine (SAMe), a naturally occurring brain metabolite, has previously been found to be effective and tolerated well in parenteral form as a treatment of major depression. To explore the antidepressant potential of oral SAMe, we conducted an open trial in 20 outpatients with major depression, including those with (n = 9) and without (n = 11) prior history of antidepressant nonresponse. The group as a whole significantly improved with oral SAMe: 7 of 11 non-treatment-resistant and 2 of 9 treatment-resistant patients experienced full antidepressant response. Side effects were mild and transient.

(REFERENCE 14 OF 29)

Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease

Morrison LD; Smith DD; Kish SJ Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, University of Toronto, Ontario, Canada

J Neurochem, Sep 1996, 67 (3) p1328-31,

S-Adenosylmethionine is an essential ubiquitous metabolite central to many biochemical pathways, including transmethylation and polyamine biosynthesis. Reduced CSF S-adenosylmethionine levels in Alzheimer's disease have been reported; however, no information is available regarding the status of S-adenosylmethionine or S-adenosylmethionine-dependent methylation in the brain of patients with this disorder. S-Adenosylmethionine concentrations were measured in postmortem brain of 11 patients with Alzheimer's disease. We found decreased levels of S-adenosylmethionine (-67 to -85%) and its demethylated product S-adenosylhomocysteine (-56 to -79%) in all brain areas examined (cerebral cortical subdivisions, hippocampus, and putamen) as compared with matched controls (n = 14). S-Adenosylmethionine and S-adenosylhomocysteine levels were normal in occipital cortex of patients with idiopathic Parkinson's disease (n = 10), suggesting that the decreased S-adenosylmethionine levels in Alzheimer's disease are not simply a consequence of a chronic, neurodegenerative condition. Reduced S-adenosylmethionine levels could be due to excessive utilization in polyamine biosynthesis. The severe reduction in levels of this essential biochemical substrate would be expected to compromise seriously metabolism and brain function in patients with Alzheimer's disease and may provide the basis for the observations of improved cognition in some Alzheimer's patients following S-adenosylmethionine therapy.

(REFERENCE 15 OF 29)

Brain S-adenosylmethionine decarboxylase activity is increased in Alzheimer's disease

Morrison LD; Bergeron C; Kish SJ Human Neurochemical Pathology Laboratory, Clarke Institute Of Psychiatry, Toronto, Ont., Canada

Neurosci Lett, May 14 1993, 154 (1-2) p141-4,

We measured the activity of S-adenosylmethionine decarboxylase (SAMDC), a key regulatory enzyme of polyamine biosynthesis, in autopsied brain from 13 patients with Alzheimer's Disease (AD). As compared with the controls, mean enzyme activity was increased by 37-96% in all seven examined brain regions with statistically significant increases in temporal cortex (+96%), frontal cortex (+69%) and hippocampus (+90%). The elevated SAMDC may have occurred as part of a generalized polyamine response to brain injury, which has been previously described in experimental animal conditions. Above-normal SAMDC activity implies increased levels/metabolism of spermidine and spermine, two polyamines which are involved in neuronal regeneration, growth factor production, and activation of excitatory N-methyl-D-aspartate preferring glutamate receptors. Our data suggest the involvement of the polyamine system in the brain reparative and/or pathogenetic mechanisms of AD.

(REFERENCE 16 OF 29)

Clinical evaluation of S-adenosyl-L-methionine versus transcutaneous electrical nerve stimulation in primary fibromyalgia

Benedetto P Di; Iona LG; Zidarich V Rehabilitation Center, Ospedale Santoro, Trieste, Italy

Curr Ther Res Feb 1993, 53 (2), p222,

The effects of S-adenosyl-L-methionine (SAMe) and transcutaneous electrical nerve stimulation (TENS) were evaluated in a 6-week controlled trial of 30 patients with primary fibromyalgia. Unlike TENS, SAMe significantly decreased the total number of tender points, had a significant beneficial effect on the subjective symptoms of pain and fatigue, and significantly reduced the scores on the Hamilton Depression and Anxiety Rating Scales and Zung's Self-Rating Scale for Depression. At the end of treatment, patients in the TENS group exhibited significantly reduced scores on the Hamilton Anxiety Scale only.

(REFERENCE 17 OF 29)

Oral S-adenosylmethionine in primary fibromyalgia-Double-blind clinical evaluation

Jacobsen S; Danneskiold-Samsoe B; Andersen RB Department of Rheumatology, Frederiksberg Hospital, Copenhagen, DK

Scand J Rheumatol,1991, 20 (4) p294-302,

S-adenosylmethionine is a relatively new anti-inflammatory drug with analgesic and anti-depressant effects. Efficacy of 800 mg orally administered s-adenosylmethionine daily versus placebo for six weeks was investigated in 44 patients with primary fibromyalgia in double-blind settings. Tender point score, isokinetic muscle strength, disease activity, subjective symptoms (visual analog scale), mood parameters and side effects were evaluated. Improvements were seen for clinical disease activity (P = 0.04), pain experienced during the last week (P = 0.002), fatigue (P = 0.02), morning stiffness (P = 0.03) and mood evaluated by Face Scale (P = 0.006) in the actively treated group compared to placebo. The tender point score, isokinetic muscle strength, mood evaluated by Beck Depression Inventory and side effects did not differ in the two treatment groups. S-adenosylmethionine has some beneficial effects on primary fibromyalgia and could be an important option in the treatment hereof.

(REFERENCE 18 OF 29)

Effect of methionine loading on 5-methyltetrahydrofolate, S-adenosylmethionine and S-adenosylhomocysteine in plasma of healthy humans

Loehrer FM; Haefeli WE; Angst CP; Browne G; Frick G; Fowler B Metabolic Unit, University Children's Hospital Basel, Switzerland

Clin Sci (Colch), Jul 1996, 91 (1) p79-86,

1.Elevated plasma homocysteine concentration, either in the fasting state or after methionine loading, is an independent risk factor for vascular disease in man. Methionine loading has been used to investigate impaired methionine metabolism, especially of the trans-sulphuration pathway, but most studies have focused on changes in homocysteine. 2.We investigated the effect of methionine excess on total plasmahomocysteine, 5-methyltetrahydrofolate (which is the active form of folate in the remethylation of homocysteine to methionine), S-adenosyl-methionine (the first metabolite of methionine) and S-adenosylmethionine) (the demethylated product of S-adenosylmethionine) over 24h in 12 healthy subjects. 3.As well as the expected increase in homocysteine (from 8.0 +/- 1.3 to 32.6 +/- 10.3 mumol/l, mean +/- SD, P < 0.001), S-adenosylmethionine showed a significant transient increase (from 37.9 +/- 25.0 to 240.3 +/- 109.2 nmol/l, P < 0.001), which correlated well with homocysteine (r2 = 0.92, P < 0.001). 5-Methyltetrahydrofolate values decreased significantly (from 23.2 +/- 7.2 to 13.1 +/- 2.9 nmol/l, P < 0.01), and gradually returned to baseline levels after 24h. No significant change over the time of measurement was found for S-adenosylhomocysteine. 4.The sequence of metabolic changes observed in this study strongly suggests that a change in either homocysteine or S-adenosylmethionine may cause a reduction in 5-methyltetrahydrofolate. This must be considered in evaluating the relationship between folate and homocysteine in vascular disease. The metabolic relationships illustrated in this study should be evaluated in the search for pathogenetic mechanisms of mild hyperhomocysteinaemia and vascular disease.

(REFERENCE 19 OF 29)

S-adenosylmethionine generation and prevention of alcoholic fatty liver by betaine

Barak AJ; Beckenhauer HC; Tuma DJ Liver Study Unit, Department of Veterans Affairs Medical Center, Omaha, NE 68105.

Alcohol, Nov-Dec 1994, 11 (6) p501-3.

Earlier studies by other investigators have shown that S-adenosylmethionine (SAM) has the capacity to attenuate liver injury in experimental animals. In a recent study in this laboratory, it was shown that when supplemental dietary betaine was given to control and ethanol-fed rats at the level of 0.50% (W/V), SAM levels were doubled in the livers of control animals and increased fivefold in livers of ethanol-fed rats. The increased levels of SAM in the livers of ethanol-fed animals protected the livers from fatty infiltration due to ethanol feeding. In this study, an attempt was made to determine the minimum level of dietary betaine that protects against the fatty infiltration. Levels of betaine at 0.05%, 0.10%, 0.25%, and 0.50% in semiliquid control and alcohol diets were tested in rats for 30 days. When hepatic betaine, SAM, and triglyceride levels were determined, it was demonstrated that only the dietary level of betaine at 0.50% supplied enough hepatic betaine to generate the level of SAM that was required to protect against the alcoholic steatosis resulting from the dietary ethanol. These results suggest that betaine, when given in sufficient amounts, may be a promising therapeutic agent in the treatment of liver disease.

(REFERENCE 20 OF 29)

S-Adenosylmethionine protects against cyclosporin A-induced alterations in rat liver plasma membrane fluidity and functions.

Galan AI, Munoz ME, Jimenez R Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain.

J Pharmacol Exp Ther 1999 Aug;290(2):774-81

We studied the effect of cyclosporin A (CyA) on liver plasma membrane (LPM) composition, fluidity, and functions and on hepatic glutathione (GS) and oxidative status. We also evaluated the ability of S-adenosylmethionine (SAMe) to antagonize the CyA-induced disturbances in rats. The animals were randomly divided into four groups and treated daily with saline, CyA vehicle, CyA, and SAMe plus CyA, respectively, for 1 week. Bile, blood, and liver samples and LPM vesicles were obtained at the end of the treatments. CyA-induced cholestasis was associated with alterations in LPM composition and fluidity. The contents of total phospholipids, phosphatidylcholine, and proteins were decreased and cholesterol and the cholesterol/phospholipid molar ratio increased. Na(+), K(+)-ATPase activity was decreased, whereas those of 5'-nucleotidase, Mg(2+)-ATPase, and gamma-glutamyltransferase increased. The hepatic contents of proteins and GS and the reduced/oxidized glutathione molar ratio were decreased and hepatic malondialdehyde increased. SAMe cotreatment 1) significantly improved or abolished the CyA-induced changes in LPM fluidity and composition and the changes in the activity of the carrier and enzymes tested, 2) counteracted the hepatic depletion of GS and proteins caused by CyA and normalized the reduced/oxidized glutathione ratio, and, as expected, 3) prevented cholestasis and the inhibitory effect of CyA on hepatobiliary transport of the major bile components. We conclude that CyA-induced cholestasis and hepatotoxicity in the rat is associated with changes in LPM composition and fluidity, liver GS depletion, and oxidative stress. SAMe cotreatment significantly improves or totally protects against these hepatotoxic effects.

(REFERENCE 21 OF 29)

Chemoprevention of rat liver carcinogenesis by S-adenosyl-L- methionine: a long-term study.

Pascale RM Marras V Simile MM Daino L Pinna G Bennati S Carta M Seddaiu MA Massarelli G Feo F,

Cancer Res (1992 Sep 15) 52(18):4979-86

Previous work has shown a consistent fall in S-adenosyl-L-methionine (SAMe) in the liver of diethylnitrosamine-initiated rats, during the development of preneoplastic lesions, in persistent nodules (PNs), and hepatocellular carcinomas. The injection of SAM into rats causes the reconstitution of the SAMe pool, coupled with growth restraint, remodeling, and apoptosis of preneoplastic cells, and inhibits the development of PNs and hepatocellular carcinomas. To evaluate if SAMe treatment causes a long-term prevention of preneoplastic and neoplastic liver lesions or merely causes a delay in their development, we evaluated the effect of a relatively short SAMe treatment on the development of preneoplastic and neoplastic lesions in a long-term study. Male Wistar rats were subjected to initiation with diethylnitrosamine, followed by selection and then by the administration of phenobarbital for 16 weeks. After selection, the rats were given i.m. injections of a purified SAMe preparation (384 micromol/kg/day) for 24 weeks. In SAMe-treated rats, a decrease in the incidence of PNs was found 6, 14, and 24-28 months after initiation. Nodule diameter started to increase rapidly again only 8 months after arresting SAMe treatment, when complete recovery of DNA synthesis in nodular cells occurred. The majority of nodules present in the liver 6-28 months after initiation belonged to the clear and acidophilic cell types, with lower percentages of mixed cell and basophilic cell types. A decrease in basophilic nodules occurred in SAMe-treated rats. Fourteen and 24-28 months after initiation hepatocellular carcinoma incidence was 11 of 12 and 10 of 10 in control rats, respectively, and only 1 of 12 and 3 of 11 in SAMe-treated rats. At the 24th-28th month all control rats had tumors identified as 2 poorly differentiated carcinomas, 6 trabecular carcinomas, or 3 adenocarcinomas, while only 2 relatively small trabecular carcinomas and 1 small glandular tumor developed in SAMe-treated rats. In 3 of 11 SAMe-treated rats, but in none of the control rats, leukemic infiltration of liver occurred 24-28 months after initiation. Leukemic infiltration of the spleen occurred in 5 and 3 control and SAMe-treated rats, respectively.

(REFERENCE 22 OF 29)

Effect of the variations of S-adenosyl-L-methionine liver content on fat accumulation and ethanol metabolism in ethanol-intoxicated rats.

Feo F, Pascale R, Garcea R, Daino L, Pirisi L, Frassetto S, Ruggiu ME, Di Padova C, Stramentinoli G

Toxicol Appl Pharmacol 1986 Apr;83(2):331-41

The protective effect of S-adenosyl-L-methionine against rat liver steatosis induced by chronic ethanol ingestion was investigated. S-Adenosyl-L-methionine given during ethanol treatment prevented steatosis and accelerated recovery from steatosis when given after ethanol withdrawal. It also caused a slight inhibition of blood ethanol consumption in both acutely and chronically intoxicated rats. About 30% inhibition of alcohol dehydrogenase, but not of the microsomal ethanol oxidation system, occurred in rats subjected to acute ethanol toxicity as well as in normal rats as a consequence of S-adenosyl-L-methionine treatment. A comparison between S-adenosyl-L-methionine and pyrazole, as concerns inhibition of ethanol oxidation and fat accumulation, revealed that a greater inhibition of ethanol metabolism by pyrazole was associated with incomplete prevention of steatosis, while a lower inhibition by S-adenosyl-L-methionine was coupled to a complete prevention. Ethanol induced a drastic decrease of reduced glutathione liver content as well as 630 and 133% increases of blood and liver acetaldehyde contents, respectively. S-Adenosyl-L-methionine treatment almost completely reconstituted the liver reduced glutathione pool and caused a large decrease of the liver and blood acetaldehyde contents. 1-Chloro-2,4-dinitrobenzene, which depletes the cellular reduced glutathione, and diethylethanolamine, an inhibitor of the phosphatidylethanolamine methylation, abolished the S-adenosyl-L-methionine-induced modifications of the reduced glutathione, acetaldehyde, and triacylglycerol contents in the liver of ethanol-treated rats. Neither S-adenosyl-L-methionine nor reduced glutathione inhibitors affected the liver acetaldehyde dehydrogenase activity. It is suggested that, although S-adenosyl-L-methionine induced a small inhibition of ethanol metabolism in the liver, its antisteatosic effect could largely depend on its role as a modulator of the reduced glutathione liver content.

(REFERENCE 23 OF 29)

Genomic abnormalities in hepatocarcinogenesis-implications

Pascale RM; Simile MM; Feo F Istituto di Patologia Generale dell' Universita di Sassari, Italy.

Anticancer Res, Sep-Oct 1993, 13 (5A) p1341-56.

Carcinogenesis is a complex process characterized by the cumulative activation of various oncogenes and the inactivation of suppressor genes. Epigenetic mechanisms are also involved. Mutational activation of ras family genes occurs in most spontaneous or carcinogen-induced liver tumors, in susceptible mice, and less frequently in preneoplastic lesions. This suggests a pathogenetic role of these changes in hepatic carcinogenesis, in the mouse. Overexpression of various growth-related genes occurs in preneoplastic tissue during rat liver carcinogenesis, but mutational activation of proto oncogenes, notably of ras family genes, seems to be a late and rare event, while c-myc amplification is a late but frequent event in both rodent and human carcinogenesis. However, mutation of the suppressor p53 gene has been found in relatively early preneoplastic lesions in rat liver, and it may be frequently seen in human hepatocellular carcinomas. The possibility that this mutation is involved in the initiation stage of liver carcinogenesis is an attractive hypothesis which needs further evaluation. DNA hypomethylation is involved in carcinogenesis, but the mechanisms underlying this effect are still elusive. Hypomethylation of growth-related genes is associated with their overexpression and this could favor overgrowth of preneoplastic liver tissue. Decrease in S-adenosyl methionine/S-adenosylhomocysteine (SAM/SAH) ratio occurs in the liver of rats fed a methyl deficient diet, which is a carcinogenic treatment, and in preneoplastic liver tissue, developing in initiated/promoted rats fed an adequate diet. The role of low SAM/SAH ratio in carcinogenesis is substantiated by the tumor chemo preventive effect of lipotropic compounds. Treatment with exogenous SAM prevents the development of preneoplastic and neoplastic lesions in rat liver. This is associated with recovery of SAM/SAH ratio, DNA methylation and inhibition of growth-related gene expression. SAM effect on prenoplastic cell growth is abolished by 5-azacytidine, a hypomethylating agent, indicating the involvement of DNA methylation. The possibility that in SAM-treated rats, methylation and inhibition of the expression of growth-related genes is implicated in growth restraint is attractive and should be further evaluated. Modulation of rat liver carcinogenesis by influencing gene expression through DNA methylation or other epigenetic mechanisms could be a new approach to chemoprevention of these tumors.

(REFERENCE 24 OF 29)

Correlation between S-adenosyl-L-methionine content and production of c-myc,

Simile MM; Pascale R; De Miglio MR; Nufris A; Daino L; Seddaiu MA; Gaspa L; Feo F Istituto di Patologia Generale, Universita di Sassari, Italy.

Cancer Lett, Apr 29 1994, 79 (1) p9-16.

Gamma-Glutamyltranspeptidase (GGT)-positive and glutathione S-transferase (placental-GST-P) positive foci were induced in male Wistar rats by initiation with diethylnitrosamine (DENA), followed by selection and phenobarbital (PB). GGT- and GST-P-positive foci occupied 20-46% and 27-68% of liver parenchyma, respectively, 5-9 weeks after initiation. A high DNA synthesis was found in GGT-positive foci. Decrease in S-adenosyl-L-methionine (SAM) level and SAM/S-adenosylhomocysteine (SAH) ratio, and overall DNA hypomethylation occurred in the liver during the development of enzyme altered foci (EAF). These parameters underwent very small and transient changes in the liver of uninitiated rats at the 5th week, when EAF occupied 0.7-1.4% of the liver. At the 9th week, high RNA transcripts of c-myc, c-Ha-ras, and c-Ki-ras were found in the liver of initiated rats, but not in that of uninitiated rats. Immunohistochemical evaluation of c-myc gene product showed overexpression in GST-P-positive cells. SAM treatment of initiated rats caused inhibition of EAF growth, recovery of SAM/SAH ratio and DNA methylation, and decrease in protooncogene expression proportional to the dose and length of treatment. Liver SAM/SAH ratio was positively correlated with DNA methylation, and negatively correlated with transcript levels of the three protooncogenes. Thus, decrease in SAM/SAH ratio and DNA hypomethylation are early features of hepatocarcinogenesis promotion in rats fed a diet containing adequate lipotrope amounts, paralleled by overexpression of growth-related genes and rapid growth. Re-establishment of a physiologic SAM level makes it possible to inhibit protooncogene expression and EAF growth and to prevent late liver lesion development.

(REFERENCE 25 OF 29)

Methyl groups in carcinogenesis: effects on DNA methylation and gene expression

Wainfan E; Poirier LA New York Blood Center, New York 10021.

Cancer Res, Apr 1 1992, 52 (7 Suppl) p2071s-2077s.

Lipotrope-deficient (methyl-deficient) diets cause fatty livers and increased liver-cell turnover and promote carcinogenesis in rodents. In rats prolonged intake of methyl-deficient diets results in liver tumor development. The mechanisms responsible for the cancer-promoting and carcinogenic properties of this deficiency remain unclear. The results of the experiments described here lend support to the hypothesis that intake of such a diet, by causing depletion of S-adenosylmethionine pools, results in DNA hypomethylation, which in turn leads to changes in expression of genes that may have key roles in regulation of growth. In livers of rats fed a severely methyl-deficient diet (MDD), lowered pools of S-adenosylmethionine and hypomethylated DNA were observed within 1 week. The extent of DNA hypomethylation increased when MDD was fed for longer periods. The decreases in overall levels of DNA methylation were accompanied by simultaneous alterations in gene expression, yielding patterns that closely resembled those reported to occur in livers of animals exposed to cancer-promoting chemicals and in hepatomas. Northern blot analysis of polyadenylated RNAs from livers of rats fed control or deficient diets showed that, after 1 week of MDD intake, there were large increases in levels of mRNAs for the c-myc and c-fos oncogenes, somewhat smaller increases in c-Ha-ras mRNA, and virtually no change in levels of c-Ki-ras mRNA. In contrast, mRNAs for epidermal growth factor receptor decreased significantly. The elevated levels of expression of the c-myc, c-fos, and c-Ha-ras genes were accompanied by selective changes in patterns of methylation within the sequences specifying these genes. Changes in DNA methylation and in gene expression induced in livers of rats fed MDD for 1 month were gradually reversed after restoration of an adequate diet. In hepatomas induced by prolonged dietary methyl deficiency, methylation patterns of c-Ki-ras and c-Ha-ras were abnormal. Although human diets are unlikely to be as severely methyl deficient as those used in these experiments, in some parts of the world intake of diets that are low in methionine and choline and contaminated with mycotoxins, such as aflatoxin, are common. Even in industrialized nations, deficiencies of folic acid and vitamin B12 are not uncommon and are exacerbated by some therapeutic agents and by substance abuse. Thus, it seems possible that interactions of diet and contaminants or drugs, by inducing changes in DNA methylation and aberrant gene expression, may contribute to cancer causation in humans.

(REFERENCE 26 OF 29)

Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease

Vendemiale G; Altomare E; Trizio T; Le Grazie C; Di Padova C; Salerno MT; Carrieri V; Albano O Institute of Medical Clinic I, University of Bari, Italy.

Scand J Gastroenterol, May 1989, 24 (4) p407-15.

S-Adenosyl-L-methionine (SAMe) is a physiologic precursor of thiols and sulfurated compounds, which are known to be decreased in patients with liver disease. The effect of its administration on the hepatic glutathione content of liver patients was investigated. Four groups of subjects were selected: a) 9 patients with alcoholic liver disease treated with SAMe (1.2 g/day orally for 6 months); b) 7 patients with non-alcoholic liver disease treated as above; c) 8 placebo-treated patients with alcoholic liver disease; and d) 15 normal subjects as a control group. Total and oxidized glutathione were assayed by high-performance liquid chromatography of liver biopsy specimens before and after the treatment period. In all patients pre-treatment hepatic glutathione was significantly decreased as compared with controls. SAMe therapy resulted in a significant increase of hepatic glutathione levels both in patients with alcoholic and in those with non-alcoholic liver diseases as compared with placebo-treated patients. SAMe may therefore exert an important role in reversing hepatic glutathione depletion in patients with liver disease.

(REFERENCE 27 OF 29)

S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.

Mato JM, Camara J, Fernandez de Paz J, Caballeria L, Coll S, Caballero A, Garcia-Buey L, Beltran J, Benita V, Caballeria J, Sola R, Moreno-Otero R, Barrao F, Martin-Duce A, Correa JA, Pares A, Barrao E, Garcia-Magaz I, Puerta JL, Moreno J, Boissard G, Ortiz P, Rodes J Department of Medicine, University of Navarra, Pamplona, Spain. jmmato@unav.es

J Hepatol 1999 Jun;30(6):1081-9

BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS: The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.

(REFERENCE 28 OF 29)

S-adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis

Duce AM; Ortiz P; Cabrero C; Mato JM Metabolismo, Nutricion y Hormonas, Fundacion, Jimenez Diaz, Madrid, Spain.

Hepatology , Jan-Feb 1988, 8 (1) p65-8.

We have measured the activity S-adenosyl-L-methionine synthetase in liver biopsies from a group of controls (n = 17) and in 26 cirrhotics (12 alcoholic and 14 posthepatic). The activity of this enzyme was markedly reduced in the group of cirrhotics (285 +/- 32 pmoles per min per mg protein) when compared with that observed in controls (505 +/- 37 pmoles per min per mg protein). No differences in S-adenosyl-L-methionine synthetase was observed between both groups of cirrhotics. Similarly, a marked reduction in the activity phospholipid methyltransferase was also observed in liver biopsies from the same group of cirrhotics (105 +/- 12 pmoles per min per mg protein) when compared with the control subjects (241 +/- 13 pmoles per min per mg protein). Again, no difference in the activity of this enzyme was observed between both groups of cirrhotics. These results indicated a marked deficiency in the metabolism of S-adenosyl-L-methionine in cirrhosis.

(REFERENCE 29 OF 29)

Reversal of extrahepatic membrane cholesterol deposition in patients with chronic liver diseases by S-adenosyl-L-methionine

Rafique S; Guardascione M; Osman E; Burroughs AK; Owen JS University Department of Medicine, Royal Free Hospital School of Medicine, London, U.K.

Clin Sci (Colch), Sep 1992, 83 (3) p353-6.

1.S-Adenosyl-L-methionine is reported to improve serum liver function tests in chronic liver disease. Because liver disease is complicated by cholesterol deposition in hepatic and extrahepatic membranes, we have assessed whether oral administration of S-adenosyl-L-methionine to patients with hepatic disease can reverse the cholesterol enrichment of their erythrocytes. 2.The mean erythrocyte cholesterol-to-phospholipid molar ratio in 13 jaundiced patients was reduced 2 weeks after oral administration of S-adenosyl-L-methionine (from 0.874 +/- 0.112 to 0.844 +/- 0.102, P < 0.05) with 10 of the patients (77%) showing a decrease. By contrast, only four of 11 untreated patients (36%) had a reduced erythrocyte cholesterol-to-phospholipid molar ratio after 2 weeks and the mean values did not differ. 3.The plasma and erythrocyte cholesterol-to-phospholipid molar ratios remained closely correlated (r = 0.77, P < 0.01) before and after treatment, suggesting that S-adenosyl-L-methionine had not acted directly on the cells but rather had improved their lipoprotein milieu. Further support for this concept was provided by following one patient, who initially failed to respond, during an additional 3 weeks of S-adenosyl-L-methionine administration. The plasma cholesterol-to-phospholipid molar ratio fell steadily from week 1 to week 5 and was accompanied by a progressive decrease in the erythrocyte cholesterol-to-phospholipid molar ratio. Moreover, the initially suppressed acetylcholinesterase activity of the erythrocyte membranes returned towards normal during this period. 4.This preliminary study is the first evidence in jaundiced patients that a drug can help to reverse the deposition of cholesterol in an extrahepatic membrane.