Effects of Oral S-Adenosyl-l-Methionine on Hepatic Glutathione in Patients with Liver Disease

Vendemiale, Gianluigi; Altomare, Emanuele; Trizio, T.; Grazie, C. Le; Padova, C. Di; Salerno, Margherita; Carrieri, V.; Albano, O

doi:10.3109/00365528909093067

Cited by 197 publications

(93 citation statements)

References 24 publications

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“…[21][22][23][24] Oral AdoMet treatment has therefore been used in animal models and in patients to restore GSH content in the liver with the aim to treat liver diseases. [25][26][27] We were interested in AdoMet not because of its role in GSH biosynthesis, 28,29 but because PRMT1 uses AdoMet as the methyl group donor for STAT1 methylation (Fig. 1D).…”

Section: Expression Of Pp2ac In Human Liver Biopsiesmentioning

confidence: 99%

S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signalingin vitro

et al. 2006

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Section: Expression Of Pp2ac In Human Liver Biopsiesmentioning

confidence: 99%

S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signalingin vitro

et al. 2006

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“…1,2 Administration of SAM in patients and animals with alcoholic liver disease restored hepatic GSH levels. 20,21 A third factor that can contribute to depletion of liver GSH level is increased GSH efflux, mediated by endotoxin. 43 Increased endotoxin levels occur in animal models of alcoholic liver disease, 44 and treatment with antibiotics attenuated liver injury.…”

Section: Figmentioning

confidence: 99%

“…Patients with alcoholic liver disease have lower hepatic GSH levels, which appears to be independent of nutritional status and probably reflects increased oxidative stress. [18][19][20] Baboons fed ethanol also chronically exhibit a lower hepatic GSH level. 21 In 1 study, rats fed ethanol in a Lieber-DeCarli diet for 16 days had markedly reduced hepatic GSH levels, 22 but another study that fed rats the same diet for 4 weeks showed little change.…”

mentioning

confidence: 99%

Effect of ethanol and high-fat feeding on hepatic ?-glutamylcysteine synthetase subunit expression in the rat

Lu¹,

Huang²,

Yang³

et al. 1999

Hepatology

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Glutathione (GSH) is important in antioxidant defense. A major determinant of the rate of GSH synthesis is the activity of the rate-limiting enzyme, ␥-glutamylcysteine synthetase (GCS). A heavy (HS) and light subunit (LS) make up GCS; oxidative stress regulates both transcriptionally. Cis-acting elements important for the oxidative stressinduced transcriptional up-regulation of both subunits are antioxidant response element (ARE) and activator protein-1 (AP-1). Nuclear factor-B (NF-B) may also regulate the heavy subunit. Chronic ethanol ingestion causes oxidative stress, increases AP-1 expression, and depletes hepatic GSH. Data conflict regarding GSH synthesis and are lacking regarding GCS subunit gene expression. We examined the effect of chronic ethanol ingestion on ARE, AP-1, and NF-B activity and GCS subunit expression. Male Wistar rats were fed an ethanol and high-fat (28.7% cal) diet intragastrically for 9 weeks. Liver GSH level fell by 40%, although GCS activity doubled. GCS-HS mRNA level doubled, whereas GCS-LS mRNA level remained unchanged. Electrophoretic mobility shift assay (EMSA) showed that binding to ARE, AP-1, and NF-B probes all increased. In conclusion, chronic ethanol ingestion increased GCS-HS expression and GCS activity by activating cis-acting elements important for transcriptional up-regulation of GCS-HS. GCS-LS mRNA level remained unchanged despite activation of ARE and AP-1, suggesting that negative transcriptional factors may be involved or the mRNA may be unstable. Despite induction in GCS activity, GSH level fell because of alterations in the other factors important in determining the steady-state GSH level. (HEPATOLOGY 1999;30:209-214.) Glutathione (GSH) is a tripeptide, ␥-glutamylcysteinylglycine, which defends against toxins and free radicals. 1 The cellular GSH level is determined by a balance of the rate of its synthesis and the rates of its utilization (conjugation) and loss (export). 2 Synthesizing GSH from its constituent amino acids involves two adenosine triphosphate-requiring enzymatic steps: forming ␥-glutamylcysteine from glutamate and cysteine, and forming GSH from ␥-glutamylcysteine and glycine. The rate of GSH synthesis is determined by the availability of cysteine and the activity of the rate-limiting enzyme, ␥-glutamylcysteine synthetase (GCS), which is subject to feedback-competitive inhibition by GSH (K i ϭ 2.3 mmol/L). 1-3 The GCS enzyme is composed of a heavy (Mr ϳ 73,000) and a light (Mr ϳ 30,000) subunit that are encoded for by different genes and dissociate under reducing conditions. 4,5 The heavy subunit (HS) exhibits all of the catalytic activity of the isolated enzyme as well as the feedback inhibition by GSH. 6 The light subunit (LS) is enzymatically inactive but plays an important regulatory function by lowering the K m of GCS for glutamate and raising the K i for GSH. 5,7 Recent studies have shown that both GCS subunits are up-regulated transcriptionally by oxidative stress. 1,[8][9][10][11][12][13] The 5Ј-flanking region of both human GCS subunits ha...

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“…13 Surgery and taurine. 2,4 in the sham-operated group was performed with the same procedure except that the bile duct was not ligated.…”

Section: Tbars Sam Had the Dose-dependent Effects Of Inhibitingmentioning

confidence: 99%

Effects ofS-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats

et al. 1997

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and hepatotoxins. [5][6][7] The drug was also found to decrease We used an animal model of extrahepatic biliary obstrucfibrogenesis in a model of experimental cirrhosis produced tion of 7 days' duration to study the production of thiobarbiby CCl 4 administration. 8 From an experimental standpoint, turic acid reactive substances (TBARS), total glutathione extrahepatic biliary obstruction caused by bile duct ligature (TG), reduced glutathione (GSH), and oxidized glutathione reliably reproduces the cholestasis syndrome, 9-11 and thus (GSSG), and the enzymatic activities of GSH-peroxidase, provides an optimal model for the study of hepatoprotective GSSG-reductase, and GSH-transferase. Four groups of six rats drugs. We used this model to investigate the hepatoprotective each were treated with saline, drug solvent, S-adenosyl-L-meeffects of SAM 12 with biochemical and histopathological analthionine (SAM) 5 mg/kg/d, subcutaneously, or SAM 10 mg/kg/ yses. The present study was designed to evaluate the protecd, subcutaneously. Extrahepatic biliary obstruction increased tive effect of two doses of SAM in a model of acute cholestasis. TBARS. SAM had the dose-dependent effects of inhibitingWe measured biochemical parameters and oxidative stress, TBARS production and increasing TG content, mainly as a which was estimated as the equilibrium between oxidating result of the increase in GSH. The activity of GSH-peroxidase factors (thiobarbituric acid reactive substances and oxidized and GSH-transferase was also significantly increased. In renal glutathione [GSSG]) and antioxidant defenses (levels of retissue these effects were statistically significant only in aniduced glutathione and activity of enzymes that control glutamals given the higher dose of SAM. In liver we found a reducthione). Through transmethylation reactions, SAM restores plasma duct. For surgery the animals were anesthetized with ethyl ether membrane fluidity in hepatocytes 3 ; transsulfuration reac-and an abdominal midline incision was made. Muscle and peritoneal tions enhance the detoxicant capacity of hepatocytes by structures were dissected to expose the bile duct, which was careincreasing the amount of endogenous cysteine, glutathione, fully dissected and ligated with braided silk at two levels.13 Surgery and taurine. 2,4 in the sham-operated group was performed with the same procedure except that the bile duct was not ligated. Recent clinical and experimental studies have shown thatEach of these two groups was divided into four treatment groups treatment with SAM has important benefits in intrahepatic (n Å 6 rats per group): 1) isotonic saline solution (pH 7.4), 2) SAM cholestasis caused by liver disease associated with acute or solvent (L-lysine, pH 7.4), 3) SAM 5 mg/kg/d (Boehringer Ingelheim chronic cholestasis, pregnancy, and the use of certain drugs Españ a SA, Barcelona, Spain), and 4) SAM 10 mg/kg/d. In groups 1 and 2 we administered a volume equivalent to that used for the higher dose of SAM. In all, 48 animals were used.In all groups the route of ...

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Effects of Oral S-Adenosyl-l-Methionine on Hepatic Glutathione in Patients with Liver Disease

Cited by 197 publications

References 24 publications

S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signalingin vitro

S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signalingin vitro

Effect of ethanol and high-fat feeding on hepatic ?-glutamylcysteine synthetase subunit expression in the rat

Effects ofS-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats

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