Role Of S-adenosylmethionine Research Articles

S-adenosylmethionine attenuates angiotensin II-induced aortic dissection formation by inhibiting vascular smooth muscle cell phenotypic switch and autophagy

It is well known that aortic dissection (AD) is a very aggressive class of vascular diseases. S-adenosylmethionine (SAM) is an autophagy inhibitor with anti-inflammatory and anti-oxidative stress effects; however, the role of SAM in AD is unknown. In this study, we constructed an animal model of AD using subcutaneous minipump continuous infusion of AngII-induced ApoE-/-mice and a cytopathic model using AngII-induced primary vascular smooth muscle cells (VSMCs) to investigate the possible role of SAM in AD. The results showed that mice in the AngII + SAM group had significantly lower AD incidence, significantly prolonged survival, and reduced vascular elastic fiber disruption compared with mice in the AngII group. In addition, SAM significantly inhibited autophagy in vivo and in vitro. Meanwhile, SAM also inhibited the cellular phenotypic switch, mainly by up regulating the expression levels of contractile marker proteins [α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α)] and down regulating the expression levels of synthetic marker proteins [osteoblast protein (OPN), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9)]. Molecularly, SAM inhibited AD formation mainly by activating the PI3K/AKT/mTOR signaling pathway. Using a PI3K inhibitor (LY294002) significantly reversed the protective effect of SAM in AngII-induced mice and VSMCs.Our study demonstrates the protective effect of SAM on mice under AngII-induced AD for the first time. SAM prevented AD formation mainly by inhibiting cellular phenotypic switch and autophagy, and activation of the PI3K/AKT/mTOR signaling pathway is a possible molecular mechanism. Thus, SAM may be a novel strategy for the treatment of AD.

Roles of S-Adenosylmethionine and Its Derivatives in Salt Tolerance of Cotton.

Salinity is a major abiotic stress that restricts cotton growth and affects fiber yield and quality. Although studies on salt tolerance have achieved great progress in cotton since the completion of cotton genome sequencing, knowledge about how cotton copes with salt stress is still scant. S-adenosylmethionine (SAM) plays important roles in many organelles with the help of the SAM transporter, and it is also a synthetic precursor for substances such as ethylene (ET), polyamines (PAs), betaine, and lignin, which often accumulate in plants in response to stresses. This review focused on the biosynthesis and signal transduction pathways of ET and PAs. The current progress of ET and PAs in regulating plant growth and development under salt stress has been summarized. Moreover, we verified the function of a cotton SAM transporter and suggested that it can regulate salt stress response in cotton. At last, an improved regulatory pathway of ET and PAs under salt stress in cotton is proposed for the breeding of salt-tolerant varieties.

The Efficacy of S-Adenosyl Methionine and Probiotic Supplementation on Depression: A Synergistic Approach.

Depression is a common and serious health issue affecting around 280 million people around the world. Suicidal ideation more frequently occurs in people with moderate to severe depression. Psychotherapy and pharmacological drugs are the mainstay of available treatment options for depressive disorders. However, pharmacological options do not offer complete cure, especially in moderate to severe depression, and are often seen with a range of adverse events. S-adenosyl methionine (SAMe) supplementation has been widely studied, and an impressive collection of literature published over the last few decades suggests its antidepressant efficacy. Probiotics have gained significant attention due to their wide array of clinical uses, and multiple studies have explored the link between probiotic species and mood disorders. Gut dysbiosis is one of the risk factors in depression by inducing systemic inflammation accompanied by an imbalance in neurotransmitter production. Thus, concomitant administration of probiotics may be an effective treatment strategy in patients with depressed mood, particularly in resistant cases, as these can aid in dysbiosis, possibly resulting in the attenuation of systemic inflammatory processes and the improvement of the therapeutic efficacy of SAMe. The current review highlights the therapeutic roles of SAMe and probiotics in depression, their mechanistic targets, and their possible synergistic effects and may help in the development of food supplements consisting of a combination of SAMe and probiotics with new dosage forms that may improve their bioavailability.

SAMS-1 coordinates HLH-30/TFEB and PHA-4/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity

ABSTRACT Dietary restriction (DR) is known to promote autophagy to exert its longevity effect. While SAMS-1 (S-adenosyl methionine synthetase-1) has been shown to be a key mediator of the DR response, little is known about the roles of S-adenosyl methionine (SAM) and SAM-dependent methyltransferase in autophagy and DR-induced longevity. In this study, we show that DR and SAMS-1 repress the activity of SET-2, a histone H3K4 methyltransferase, by limiting the availability of SAM. Consequently, the reduced H3K4me3 levels promote the expression and activity of two transcription factors, HLH-30/TFEB and PHA-4/FOXA, which both regulate the transcription of autophagy-related genes. We then find that HLH-30/TFEB and PHA-4/FOXA act collaboratively on their common target genes to mediate the transcriptional response of autophagy-related genes and consequently the lifespan of the animals. Our study thus shows that the SAMS-1-SET-2 axis serves as a nutrient-sensing module to epigenetically coordinate the activation of HLH-30/TFEB and PHA-4/FOXA transcription factors to control macroautophagy/autophagy and longevity in response to DR. Abbreviations: ChIP: chromatin immunoprecipitation; ChIP-seq: chromatin immuno precipitation-sequencing; COMPASS: complex of proteins associated with Set1; DR: dietary restriction; GO: gene ontology; SAM: S-adenosyl methionine; SAMS-1: S-adenosyl methionine synthetase-1; TSS: transcription start site; WT: wild-type.

145 Nutritional Advances in Fetal and Neonatal Development: Methyl Donors

Abstract The objective of this presentation is to discuss and review research on methyl donors in the developmental programming of dairy cattle. One-carbon metabolism is catalyzed by several enzymes in the presence of dietary micronutrients, including methionine, choline, betaine, and folate, and generates S-adenosylmethionine. S-adenosylmethionine is crucial for numerous cellular functions such as DNA and histone methylation as well as protein synthesis. Despite the biological role of S-adenosylmethionine, there is a limited understanding of the impact of dietary methyl donors’ supply to pregnant dairy cows and neonatal calves. The majority of research related to methyl donors in fetal and neonatal development and physiology has been generated supplying methyl donors to dairy cows during the end of gestation. The results from recent studies are not conclusive, but overall they indicate that methyl donors supply during the end of pregnancy enhance calf performance and ameliorate immune response. A better understanding of the impact of methyl donors may offer new ways to augment development, performance and immune function of growing replacement heifers.

Serine Biosynthesis Pathway Supports MYC-miR-494-EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells.

Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.

4.68 Role of S-Adenosyl Methionine, Zinc, and Magnesium in Management of Pediatric Depression and ADHD

4.68 Role of S-Adenosyl Methionine, Zinc, and Magnesium in Management of Pediatric Depression and ADHD

The use of SAMe in chemotherapy-induced liver injury.

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure in the Western world. Chemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI. For this reason, patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate and which drug doses should be modified. S-adenosylmethionine (SAMe) is an endogenous agent derived from methionine. Its supplementation is effective in the treatment of liver disease, in particular intrahepatic cholestasis (IHC). The target of this review is to analyze the mechanisms of hepatotoxicity of the principal anticancer agents and the role of SAMe in the prevention of this complication.

Role of S-Adenosylmethionine (SAMe) in the Treatment of Osteoarthritis

Role of S-Adenosylmethionine (SAMe) in the Treatment of Osteoarthritis

Protective Role of S-Adenosyl Methionine (SAMe) in Cadmium Induced Toxicopathological Changes in Wistar Rats

Cadmium is considered to be one of the most toxic substances in the environment due to its wide range of organ toxicity and long elimination half-life. SAMe is recognized as the major methyl-donor for essential methylation reactions that occur in all living organisms. SAMe has been increasingly utilized as a therapeutic agent in liver and neurological disorders recently. The present study has been devised to explore the alleviating effects of SAMe in cadmium induced toxicopathological changes in rats. The rats were divided into four experimental groups: group I formed the control, group II animals were given cadmium chloride @ 200ppm in distilled water, orally, group III animals were given SAMe @ 1 mg/kg body weight, orally and group IV were given both CdCl2 and SAMe. Six rats from each group were humanely sacrificed at 30th, 60th and 90th day. The quantitative data of body weight, absolute organ weight, cadmium content and oxidative stress parameters was analyzed by Duncan's multiple range tests The group II animals showed most of the pathological changes compared to the rest of the group. The magnitude of lesions in various organs was lesser in group IV where SAMe was given. The severity of lesions increased with the advancement of experiment; most severe pathological changes occurring on the 90th day. The level of cadmium residue in liver and kidneys of rats was also found to be increasing with the time in group II and IV; with group IV showing a relatively lesser increase. Similarly the evaluation of oxidative stress parameters reflected the detrimental effect of cadmium in group II and an alleviating effect of SAMe in group IV. Based on the results obtained, SAMe is found to alleviate the toxicopathological effects of cadmium in rats which needs to be further explored.

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

S-adenosyl-L-methionine (SAM) is the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. SAM level in the organism decreases with aging and restoring the original levels through exogenous supplementation is an important tool for the improvement of many vital functions. Indeed, SAM deficiency may contribute to the onset of several diseases, i.e. depression, liver diseases, osteoarthritis and senile neurological disorders such as Alzheimer’s and Parkinson’s diseases. Recent evidences indicate that SAM may have an involvement in oxidative stress, a process which typically involves an alteration of cellular sulfur amino acids homeostasis. SAM is not only the principal methyl donor, but also a precursor of glutathione, the major endogenous antioxidant, whose role in counteracting oxidative stress is well known. In this review we will highlight the role of SAM not just as a methyl-donor but also as a regulator of different metabolic pathways involved in the antioxidant response in brain related disorders.

S-adenosylmethionine reduces airway inflammation and fibrosis in a murine model of chronic severe asthma via suppression of oxidative stress.

Increased oxidative stress has an important role in asthmatic airway inflammation and remodeling. A potent methyl donor, S-adenosylmethionine (SAMe), is known to protect against tissue injury and fibrosis through modulation of oxidative stress. The aim of this study was to evaluate the effect of SAMe on airway inflammation and remodeling in a murine model of chronic asthma. A mouse model was generated by repeated intranasal challenge with ovalbumin and Aspergillus fungal protease twice a week for 8 weeks. SAMe was orally administered every 24 h for 8 weeks. We performed bronchoalveolar lavage (BAL) fluid analysis and histopathological examination. The levels of various cytokines and 4-hydroxy-2-nonenal (HNE) were measured in the lung tissue. Cultured macrophages and fibroblasts were employed to evaluate the underlying anti-inflammatory and antifibrotic mechanisms of SAMe. The magnitude of airway inflammation and fibrosis, as well as the total BAL cell counts, were significantly suppressed in the SAMe-treated groups. A reduction in T helper type 2 pro-inflammatory cytokines and HNE levels was observed in mouse lung tissue after SAMe administration. Macrophages cultured with SAMe also showed reduced cellular oxidative stress and pro-inflammatory cytokine production. Moreover, SAMe treatment attenuated transforming growth factor-β (TGF-β)-induced fibronectin expression in cultured fibroblasts. SAMe had a suppressive effect on airway inflammation and fibrosis in a mouse model of chronic asthma, at least partially through the attenuation of oxidative stress and TGF-β-induced fibronectin expression. The results of this study suggest a potential role for SAMe as a novel therapeutic agent in chronic asthma.

Serum S-adenosylmethionine, but not methionine, increases in response to overfeeding in humans.

Background:Plasma concentration of the methyl donor S-adenosylmethionine (SAM) is linearly associated with body mass index (BMI) and fat mass. As SAM is a high-energy compound and a sensor of cellular nutrient status, we hypothesized that SAM would increase with overfeeding.Methods:Forty normal to overweight men and women were overfed by 1250 kcal per day for 28 days.Results:Serum SAM increased from 106 to 130 nmol/l (P=0.006). In stratified analysis, only those with weight gain above the median (high-weight gainers; average weight gain 3.9±0.3 kg) had increased SAM (+42%, P=0.001), whereas low-weight gainers (weight gain 1.5±0.2 kg) did not (Pinteraction=0.018). Overfeeding did not alter serum concentrations of the SAM precursor, methionine or the products, S-adenosyl-homocysteine and homocysteine. The SAM/SAH (S-adenosylhomocysteine) ratio was unchanged in the total population, but increased in high-weight gainers (+52%, P=0.006, Pinteraction =0.005). Change in SAM correlated positively with change in weight (r=0.33, P=0.041) and fat mass (r=0.44, P=0.009), but not with change in protein intake or plasma methionine, glucose, insulin or low-density lipoprotein (LDL)-cholesterol.Conclusion:Overfeeding raised serum SAM in proportion to the fat mass gained. The increase in SAM may help stabilize methionine levels, and denotes a responsiveness of SAM to nutrient state in humans. The role of SAM in human energy metabolism deserves further attention.

Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the 'key switch' between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH.

Glucocorticoid-induced S-Adenosylmethionine Enhances the Interferon Signaling Pathway by Restoring STAT1 Protein Methylation in Hepatitis B Virus-infected Cells

Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon α (IFN-α). An alternative approach to increase the response rate of IFN-α might be to immunologically stimulate the host with glucocorticoids (GCs) before treatment with IFN-α, but the underlying mechanism remains unclear. We hypothesized that the GCs enhance IFN signaling by inducing S-adenosylmethionine (AdoMet) when hepatitis B virus (HBV) replication was effectively suppressed by IFN-α. Here, we investigated the effect of GCs and IFN-α on AdoMet production and methionine adenosyltransferase 1A (MAT1A) expression in vitro. Furthermore, we determined whether post-transcriptional regulation is involved in HBV-repressed MAT1A expression and AdoMet production induced by dexamethasone (Dex). We found that AdoMet homeostasis was disrupted by Dex and that Dex directly regulated MAT1A expression by enhancing the binding of the glucocorticoid receptor (GR) to the glucocorticoid-response element (GRE) of the MAT1A promoter. HBV reduced AdoMet production by increasing methylation at GRE sites within the MAT1A promoter. The X protein of hepatitis B virus led to hypermethylation in the MAT1A promoter by recruiting DNA methyltransferase 1, and it inhibited GR binding to the GRE in the MAT1A promoter. Dex could increase an antiviral effect by inducing AdoMet production via a positive feedback loop when HBV is effectively suppressed by IFN-α, and the mechanism that involves Dex-induced AdoMet could increase STAT1 methylation rather than STAT1 phosphorylation. These findings provide a possible mechanism by which GC-induced AdoMet enhances the antiviral activity of IFN-α by restoring STAT1 methylation in HBV-infected cells.

S-adenosylmethionine Levels Regulate the Schwann Cell DNA Methylome

Axonal myelination is essential for rapid saltatory impulse conduction in the nervous system, and malformation or destruction of myelin sheaths leads to motor and sensory disabilities. DNA methylation is an essential epigenetic modification during mammalian development, yet its role in myelination remains obscure. Here, using high-resolution methylome maps, we show that DNA methylation could play a key gene regulatory role in peripheral nerve myelination and that S-adenosylmethionine (SAMe), the principal methyl donor in cytosine methylation, regulates the methylome dynamics during this process. Our studies also point to a possible role of SAMe in establishing the aberrant DNA methylation patterns in a mouse model of diabetic neuropathy, implicating SAMe in the pathogenesis of this disease. These critical observations establish a link between SAMe and DNA methylation status in a defined biological system, providing a mechanism that could direct methylation changes during cellular differentiation and in diverse pathological situations.

The combined effects of S-adenosylmethionine and chloroquine on hepatocellular carcinoma during acute ischemic hypoxia

Objective To investigate the role of S-adenosylmethionine (SAMe) during ischemia/hypoxia in hepatocellular carcinoma and its underlying mechanism through autophagy inhibition by chloroquine (CQ).Methods Real-time PCR measured the expression of Beclin 1,and quantitative analysis of autophagy was performed with fluorescent microscope on acridine orange staining.The cellular viability was detected by the CCK8 method,the LC3 protein was detected by Western blot,and apoptosis was detected by AnnexinV/PI flow cytometry.Results The cellular viability under ischemia/hypoxia increased about 20％ ～30％.SAMe induced autophagy in the hepatoma cell line HepG2,and the level of autophagy in fluorescent intensity and real-time PCR of Beclin 1 increased about 3.2 and 3.5 times,respectively.SAMe significantly inhibited the proliferation of HepG2,especially in the environment of ischemia/hypoxia.The cellular viability under SAMe treatment only and SAMe-treatment followed by ischemia/hypoxia decreased about 30 ％ and 70 ％,respectively,and cellular apoptosis increased about 24％ and 40％,respectively,over blank control.After autophagy inhibition,the proliferation of HepG2 decreased about 15 ％ ～ 30 ％ and cellular apoptosis increased about 7 ％ ～ 16 ％.Conclusions SAMe inhibited the proliferation of HepG2,and autophagy may be a protective factor during acute ischemic hypoxia. Key words: Hepatocellular carcinoma; Autophagy; S-adenosylmethionine; Chloroquine

Abstract 1038: Plasma S-adenosylmethionine levels, genetic polymorphisms of DNMT1 and DNMT3A, and LINE-1 DNA methylation among Chinese in Singapore

Abstract Genome-wide DNA hypomethylation is believed to be one of the early molecular abnormalities in carcinogenesis and there is great interest in identifying traits and exposures that contribute to genomic DNA hypomethylation. One-carbon metabolism has been extensively studied in relation to cancer because its key metabolite, S-adenosylmethionine (SAM), is a methyl donor for DNA methylation reactions which are catalyzed by DNA methyltransferases (DNMTs). Here we have tested the hypothesis that plasma SAM levels alone or in combination with DNMT1 and DNMT3A genetic variation are associated with DNA methylation levels at long interspersed nucleotide element-1 (LINE-1), a surrogate marker for genome-wide DNA methylation. A total of 440 healthy Singapore Chinese adults (192 men and 248 women, 46-77 y) were selected from participants of the Singapore Chinese Health Study, who donated biospecimens during 1994-1998. Plasma SAM levels and LINE-1 DNA methylation were measured using stored blood samples. We chose tagging SNPs of the DNMT1 and DNMT3A genes for the Han Chinese population based on the HapMap database and literature search. LINE-1 methylation was compared among quartiles of plasma SAM levels and DNMT genotypes using multivariate linear regression methods in men and women separately. We also evaluated the effect modification of DNMT genotypes on the association between plasma SAM levels and LINE-1 methylation. Age-adjusted LINE-1 methylation was significantly higher in men (mean=78.1%, 95%CI=77.7-78.4%) than in women (mean=77.4%, 95%CI=77.1-77.7%, p=0.002). Higher LINE-1 methylation was associated with older age in men (ptrend=0.004) but not in women. LINE-1 methylation was significantly lower among those with the lowest quartile of plasma SAM compared with those with higher plasma SAM in both men and women. LINE-1 methylation increased with increasing plasma SAM levels, with a plateau at 55 nmol/L SAM in men and 50 nmol/L in women. Compared with men carrying wildtype genotype, men carrying at least one copy of the variant DNMT1 rs2114724 allele had higher LINE-1 methylation (ptrend=0.007), while men carrying at least one copy of the variant DNMT3A rs7581217 allele had lower LINE-1 methylation (ptrend=0.004). No similar associations were observed in women. When stratified by DNMT1 rs2114724 genotype, a positive association between plasma SAM levels and LINE-1 methylation was present among men with low LINE1 methylation and wildtype genotype, but not with variant genotypes of DNMT1. DNMT1 and DNMT3A haplotypes were not associated with LINE-1 methylation in either men or women. Our findings support a role of SAM on genome-wide DNA methylation. Further, DNMT1 genetic polymorphisms may exert modifying effect on the SAM-DNA methylation association. The study was supported by grant R01 CA144034. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1038. doi:1538-7445.AM2012-1038

The Role of Abnormalities Related to the One Carbon Cycle in Depression and Schizophrenia

This paper reviews our present knowledge of the role of the one-carbon cycle in mood disorder and schizophrenia with particular attention to S-adenosyl methionine (SAM). After an historical introduction the clinical data is first reviewed of the anti-depressant action of SAM, in particular a survey of double blind placebo-controlled trials. Then follows an account of the biochemical parameters of the action of SAM, in particular the role of folic acid and 5-methyltetrahydrofolate (vitamin B9), polyamines, homocysteine, together with epigenetic studies. In schizophrenia the effect of oral l-methionine on worsening the symptoms of some chronic schizophrenics has been known since 1961. Recent epigenetic research covered has addressed the mechanism of this reaction. This includes the role of SAM in modulating DNA methyltransferase-1 mRNA activity, cytosine 5-methylation, spine numbers and the expression of mRNAs encoding for reelin and GAD67 in GABAergic neurons in the frontal cortex in schizophrenia. There is also evidence that marker D8S542 located within the methionine sulfoxide reductase (MSRA) gene may be involved in schizophrenia as well as 677C > T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. The possible roles of homocysteine and methionine S-adenosyl transferase kinetics are also discussed.

Vitamin-dependent methionine metabolism and alcoholic liver disease.

Emerging evidence indicates that ethanol-induced alterations in hepatic methionine metabolism play a central role in the pathogenesis of alcoholic liver disease (ALD). Because malnutrition is a universal clinical finding in this disease and hepatic methionine metabolism is dependent upon dietary folate and vitamins B-6 and B-12, ALD can be considered an induced nutritional disorder that is conditioned by alcohol abuse. The present review describes the etiologies of these 3 vitamin deficiencies in ALD and how they interact with chronic ethanol exposure to alter hepatic methionine metabolism. Subsequent sections focus on molecular mechanisms for the interactions of aberrant methionine metabolism with ethanol in the pathogenesis of ALD, in particular the role of S-adenosylmethionine (SAM) in regulating the epigenetic expressions of genes relevant to pathways of liver injury. The review will conclude with descriptions of studies on the efficacy of SAM in the treatment of ALD and with discussion of potentially fruitful future avenues of research.