S-腺苷蛋氨酸对梗阻性黄疸病人肝蛋白质合成的影响

目的:研究S-腺苷蛋氨酸(SAMe)对梗阻性黄疸病人肝蛋白质合成的影响. 方法:将40例梗阻性黄疸病人随机分为治疗组和对照组.治疗组病人给予SAMe静脉滴注,1g/d,连续3d;对照组不予任何保肝药物.观察SAMe治疗后3d对梗阻性黄疸病人血清清蛋白、前清蛋白、转铁蛋白、天冬氨酸氨基转移酶、谷氨酸氨基转移酶、碱性磷酸酶、谷酰转肽酶等肝功能的影响. 结果:与对照组比较,治疗组病人在胆道梗阻解除前SAMe能显著升高血清前清蛋白和转铁蛋白浓度(P＜0.01),并能显著降低天冬氨酸氨基转移酶、谷氨酸氨基转移酶等指标(P＜0.01),但对总胆红素、直接胆红素、碱性磷酸酶、谷酰转肽酶等的影响无显著性差异(P＞0.05).结论:SAMe能促进梗阻性黄疸病人肝蛋白质合成,降低转氨酶,改善肝功能.     

S-adenosyl-L-methionine: its role in the treatment of liver disorders

S-Adenosyl-L-methionine (SAMe) exerts many key functions in the liver, including serving as a precursor for cysteine, 1 of 3 amino acids of glutathione--the major physiologic defense mechanism against oxidative stress. SAMe is particularly important in opposing the toxicity of free oxygen radicals generated by various pathogens, including alcohol, which cause oxidative stress largely by the induction of cytochrome P4502E1 (CYP2E1) and by its metabolite acetaldehyde. SAMe also acts as the main methylating agent in the liver. The precursor of SAMe is methionine, one of the essential amino acids, which is activated by SAMe-synthetase (EC 2.5.1.6). Unfortunately, the activity of this enzyme is significantly decreased as a consequence of liver disease. Because of decreased utilization, methionine accumulates and, simultaneously, there is a decrease in SAMe that acquires the status of an essential nutrient and therefore must be provided exogenously as a supernutrient to compensate for its deficiency. Administration of this innocuous supernutrient results in many beneficial effects in various tissues, mainly in the liver, and especially in the mitochondria. This was shown in alcohol-fed baboons and in other experimental models of liver injury and in clinical trials, some of which are reviewed in other articles in this issue.     

Role of autophagy in the pathogenesis of liver diseases

Autophagy is a self-digestion process that plays an important role in the development, differentiation and homeostasis of cells, helping their survival during starvation and hypoxia. Accumulated mutant proteins in the endoplasmic reticulum can be degraded by autophagy in alpha-1 antitrypsin deficiency. Hepatitis C and B virus may exploit the autophagy pathway to escape the innate immune response and to promote their own replication. Autophagy is decreased in response to chronic alcohol consumption, likely due to a decrease in 5'-adenosine monophosphate-activated protein kinase, increase in mTOR activity and due to an alteration in vesicle transport in hepatocytes. In obesity and alcoholic liver disease the decreased function of autophagy causes formation of Mallory-Denk bodies and cell death. The deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress, and to progression of liver disease. Autophagy defect in hepatocellular carcinoma suggests that it can serve a tumor-suppressor function. The autophagy protein Beclin-1 levels have prognostic significance in liver tumors. Understanding of the molecular mechanism and the role of autophagy may lead to more effective therapeutic strategies in liver diseases in the future.     

Effect of dietary zinc deficiency on protein synthesis in cell-free systems isolated from rat liver

This study presents evidence for the direct involvement of zinc in the translation of polypeptide chains in rat liver. Cell-free systems consisting of polyribosomes and fractions, enriched with aminoacyl-tRNA synthetase for incorporation of amino acids into trichloroacetic acid-insoluble proteins, were prepared from livers of three populations of rats: 1) rats fed ad libitum a diet containing 25 ppm zinc; 2) rats fed a diet containing less than 1 ppm zinc; and 3) rats pair fed to the zinc-deficient group a diet containing 25 ppm zinc. Group 2 showed typical signs of zinc deficiency, including decreased bone zinc. The protein synthetic ability of systems isolated from zinc-deficient rats was considerably depressed, resulting in incorporation of 59-69% of the amino acids incorporated by systems from pair-fed rats and 54-59% of those incorporated by ad libitum-fed control animals. This effect was significant after only 14 d of the dietary regimen. Experiments performed by mixing polyribosomes and synthetase fractions from the different groups indicated that a defect is located in the synthetase fraction. Acylation of tRNA by the synthetase fraction also was assayed and found to be 69-90% of that in zinc-sufficient preparations. It is suggested that one or more of the aminoacyl-tRNA synthetase enzymes from the rat liver may be zinc dependent.     

Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium.

The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of S-Adenosyl-L-Methionine (SAMe) in the Treatment of Alcoholic Liver Disease" in Bethesda, Maryland, September 2001. Alcoholic liver disease (ALD) is a major cause of illness and death in the United States. Oxidant stress plays a key role in pathogenesis of liver disease. S-Adenosyl-L-methionine, a dietary supplement, is the methyl donor for biochemical methylation reactions and a precursor of glutathione, the main hepatocellular antioxidant. S-Adenosyl-L-methionine has been shown to attenuate liver injury caused by alcohol and other hepatotoxins in some animal models. Understanding the mechanisms by which SAMe attenuates liver injury caused by alcohol may provide useful information for full-scale human clinical trials. For this symposium, seven speakers were invited to address the following issues: (1) impaired methionine metabolism in alcoholic liver injury; (2) regulation of liver function by SAMe; (3) folate deficiency, methionine metabolism, and alcoholic liver injury; (4) attenuating effect of SAMe on ALD in experimental animals; (5) SAMe and mitochondrial glutathione depletion in ALD; (6) SAMe and cytokine production in liver injury; and (7) role of SAMe in the prevention of hepatocarcinogenesis. The presentations of this symposium support the suggestion that SAMe may have potential to treat ALD by (1) acting as a precursor of antioxidant glutathione, (2) repairing mitochondrial glutathione transport system, (3) attenuating toxic effects of proinflammatory cytokines, and (4) increasing DNA methylation. Further studies are required to evaluate the safety and effectiveness of SAMe treatment.     

Ethanol and liver injury: aspects relating to hepatic protein synthesis

Throughout the world ethanol consumption is probably one of the most important and widespread environmental factors in inducing human liver disease. Although it has been established that ethanol is a potent hepatotoxic agent, the mechanism/s by which it acts upon the liver is/are not clear. This review focuses upon one aspect of ethanol and its effect on liver metabolism, that relating to hepatic protein synthesis. Experimental studies have been reviewed and the current views regarding the action of ethanol upon hepatic protein synthesis are presented. The overall picture still remains to be clarified.     

Ischemia-reperfusion injury of the liver

There is no single factor responsible for liver injury after its temporary ischemia and reperfusion. We deal with a mosaic of biochemical processes, in which a number of cells, mediators and enzymatic systems take part. The mechanism of liver injury remains far from full explanation.     

Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence

Major depression remains difficult to treat, despite the wide array of registered antidepressants available. In recent years there has been a surge in the popularity of natural or alternative medications. Despite this growing popularity, there is limited evidence for the effectiveness of many of these natural treatments. S-adenosyl-L-methionine (SAMe) is one of the better studied of the natural remedies. SAMe is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. Derived from the amino acid L-methionine through a metabolic pathway called the one-carbon cycle, SAMe has been postulated to have antidepressant properties. A small number of clinical trials with parenteral or oral SAMe have shown that, at doses of 200-1600 mg/d, SAMe is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses. SAMe may have a faster onset of action than do conventional antidepressants and may potentiate the effect of tricyclic antidepressants. SAMe may also protect against the deleterious effects of Alzheimer disease. SAMe is well tolerated and relatively free of adverse effects, although some cases of mania have been reported in bipolar patients. Overall, SAMe appears to be safe and effective in the treatment of depression, but more research is needed to determine optimal doses. Head-to-head comparisons with newer antidepressants should help to clarify SAMe's place in the psychopharmacologic armamentarium.     

Effect of S-adenosyl-L-methionine administration on plasma levels of sulphur-containing amino acids in patients with liver cirrhosis

An impaired transsulphuration pathway has been described in patients with liver cirrhosis. The defective metabolic step is located at the site of S-adenosyl-L-methionine (SAMe) formation from methionine. In a placebo-controlled study, we measured the fasting plasma levels of sulphur-containing amino-acids in cirrhotic patients with hypermethioninemia and/or severe hepatocellular failure, during treatment with exogenous SAMe (1.2 g i.v. for 3 days, followed by an oral administration of 1.2 g for an additional 30 days; 8 cases) or saline and placebo tablets (8 cases). All subjects were initially treated during hospital admission, and completed the oral study as out-patients. In patients given SAMe, long-term treatment doubled the plasma concentration of the secondary sulphur-containing amino acid cystine (from 36 [SD 18] mumol.l(-1) to 67 [36]) and taurine (from 42 [13] mumol.l(-1) to 89 [33]), which were on average low-normal at baseline, without any change in the concentration of methionine, of neutral amino acids, and of polyamines. No changes in plasma amino acids were observed in the control group. Two-factor, repeated measures of analysis of variance revealed differences between SAMe- and placebo-treated patients, consistent with an effect of long-term SAMe administration on secondary sulphur-containing amino acids. The potential therapeutic advantage of such treatment remains to be determined in clinical studies.     

细胞外组蛋白在急性肝衰竭发病机制中的研究进展

急性肝衰竭是由多种因素引起的短时间内肝脏发生损害的严重临床综合征,死亡率高,且无特效疗法.细胞外组蛋白是一种新发现的炎性介质或危险信号分子,在启动及加重肝损伤中有着重要的作用.本文阐述了细胞外组蛋白结构、生物学特性、来源及导致细胞毒性的机制,从多方面探讨细胞外组蛋白在急性肝衰竭发病中的作用机制.