Restoration Of Glutathione Levels Research Articles

Protective Effects of 2-Methoxyestradiol on Acute Isoproterenol-Induced Cardiac Injury in Rats

Myocardial injury (MI) is an important pathological driver of mortality worldwide., and arises as a result of imbalances between myocardial oxygen demand and supply. In MI, oxidative stress often leads to inflammatory changes and apoptosis. Current therapies for MI are known to cause various adverse effects. Consequently, the development of new therapeutic agents with a reduced adverse event profile is necessary. In this regard, 2-methoxyestradiol (2ME), the metabolic end-product of oestradiol, possesses anti-inflammatory and antioxidant properties. The aim of this research is to assess the impact of 2ME on cardiac injury caused by isoproterenol (ISO) in rats. Animals were separated into six groups; controls, and those receiving 2ME (1 mg/kg), ISO (85 mg/kg), ISO + 2ME (0.25 mg/kg), ISO + 2ME (0.5 mg/kg), and ISO + 2ME (1 mg/kg). 2ME significantly attenuated ISO-induced changes in electrocardiographic changes and the cardiac histological pattern. This compound also decreased lactate dehydrogenase activity, creatine kinase myocardial band and troponin levels. The ability of 2ME to act as an antioxidant was shown by a decrease in malondialdehyde concentration, and the restoration of glutathione levels and superoxide dismutase activity. Additionally, 2ME antagonized inflammation and cardiac cell apoptosis, a process determined to be mediated, at least partially, by suppression of Gal-3/TLR4/MyD88/NF-κB signaling pathway. 2ME offers protection against acute ISO-induced MI in rats and offers a novel therapeutic management option.

Antioxidant, Antiapoptotic, and Anti-Inflammatory Effects of Hesperetin in a Mouse Model of Lipopolysaccharide-Induced Acute Kidney Injury.

Sepsis is a severe inflammatory condition that can cause organ dysfunction, including acute kidney injury (AKI). Hesperetin is a flavonoid aglycone that has potent antioxidant and anti-inflammatory properties. However, the effect of hesperetin on septic AKI has not yet been fully investigated. This study examined whether hesperetin has a renoprotective effect on lipopolysaccharide (LPS)-induced septic AKI. Hesperetin treatment ameliorated histological abnormalities and renal dysfunction in LPS-injected mice. Mechanistically, hesperetin attenuated LPS-induced oxidative stress, as evidenced by the suppression of lipid and DNA oxidation. This beneficial effect of hesperetin was accompanied by downregulation of the pro-oxidant NADPH oxidase 4, restoration of glutathione levels, and activation of antioxidant enzymes. This flavonoid compound also inhibited apoptotic cell death via suppression of p53-dependent caspase-3 pathway. Furthermore, hesperetin alleviated Toll-like receptor 4-mediated cytokine production and macrophage infiltration. Our findings suggest that hesperetin ameliorates LPS-induced renal structural and functional injury through suppressing oxidative stress, apoptosis, and inflammation.

Hispidulin Ameliorates Endotoxin-Induced Acute Kidney Injury in Mice.

Lipopolysaccharide (LPS) is an endotoxin that plays a crucial role in septic acute kidney injury (AKI). Hispidulin is a natural flavonoid that possesses various biological activities. Recent studies have shown that hispidulin administration alleviates various inflammatory diseases in animal models. This study aimed to investigate the renoprotective effect of hispidulin on LPS-induced AKI. Male C57BL/6 mice were administered LPS (10 mg/kg) with or without hispidulin (50 mg/kg). Hispidulin administration attenuated renal dysfunction, histological alterations, and the upregulation of neutrophil gelatinase-associated lipocalin. This flavonoid also reduced cytokine production and Toll-like receptor 4 expression, inhibited nuclear factor-κB and mitogen-activated protein kinase cascades, and alleviated immune cell infiltration. The oxidation of lipids and DNA was also inhibited by hispidulin administration. This antioxidant effect of hispidulin was associated with the downregulation of NADPH oxidase 4, the activation of catalase and superoxide dismutase activities, and the restoration of glutathione levels. Moreover, hispidulin administration attenuated tubular cell apoptosis by inhibiting caspase-3 pathway. These data suggest that hispidulin ameliorates endotoxin-induced kidney injury by suppressing inflammation, oxidative stress, and tubular cell death.

Antioxidant effect of cortexin, cerebrolysin and actovegin in rats with chronic cerebrovascular insufficiency

To compare the antioxidant effects of cortexin, cerebrolysin and actovegin in rats with chronic brain ischemia. Chronic brain ischemia was modeled in male rats by 50% stenosis of the common carotid arteries. Forty days after surgery, the animals received 2 ten-day courses of therapy, separated by a break of 10 days. Placebo, cortexin (0.3, 1 and 3 mg/kg), cerebrolysin (0.8, 2.5 and 7.5 ml/kg) and actovegin (5 ml/kg) were administered to animals as treatment. The concentration of malondialdehyde (MDA) in the homogenates was determined by the reaction with thiobarbituric acid, the concentration of reduced glutathione was determined by the reduction reaction of 5.5-dithiobis- (2-nitrobenzoic acid); determination of catalase activity, as well as the content of lactate and pyruvate, by commercially available reagent kits. The activity of superoxide dismutase (SOD) was determined by the photometric method based on an assessment of the degree of inhibition of the epinephrine oxidation reaction. All reactions were carried out in triplicates. Modeling of chronic brain ischemia led to the statistically significant decrease in the content of lactate and pyruvate (p<0.001, when compared with the control group), which was not accompanied by a significant decrease in their ratio (p>0.05), as well as to the decrease in SOD, catalase activity, restored glutathione and increase in MDA concentrations. Compared with the control group, in the groups that received cortexin at a dose of 3 mg/kg/day, cerebrolysin at a dose of 7.5 ml/kg/day and actovegin at a dose of 5 ml/kg/day, there were an increase in the content of lactate and pyruvate (without a significant change in their ratio), restoration of glutathione levels and the activity of SOD and, to a lesser extent, catalase, combined with a decrease in the concentration of MDA. Course administration of cortexin (3 mg/kg), cerebrolysin (7.5 ml/kg) and, to a lesser extent, actovegin (5 ml/kg) has a positive effect on the state of the antioxidant system of the brain in rats with chronic brain ischemia.

Melatonin protects against behavioral deficits, dopamine loss and oxidative stress in homocysteine model of Parkinson's disease

AimHyperhomocysteinemia and homocysteine (Hcy) mediated dopaminergic neurotoxicity is a matter of concern in the pathophysiology of Parkinson's disease (PD). Our previous study established the involvement of oxidative stress in the substantia nigra (SN) of Hcy rat model of PD; however, the role of antioxidants, such as melatonin, was not tested in this model. Main methodsMelatonin (10, 20 and 30mg/kg, i.p.) was administered to rats injected with Hcy in right SN (1.0μmol in 2μl saline) to investigate its potency in attenuating the behavioral abnormalities, dopamine depletion and oxidative stress prompted by Hcy. Key findingsTreatment of melatonin protected against nigral dopamine loss and replenished the striatal dopamine loss that resulted in amelioration of rotational behavioral bias in Hcy denervated animals. Melatonin administration significantly improved mitochondrial complex-I activity and protected the SN neurons from the toxic insults of oxidative stress induced by Hcy. Amelioration of oxidative stress by melatonin in Hcy-infused SN was bought by dose-dependently scavenging of hydroxyl radicals, restoration of glutathione level and elevation in the activity of antioxidant enzymes. SignificanceThe observations bring into light the significant neuroprotective potentials of melatonin in Hcy model of PD which is attributed to the attenuation of oxidative stress in SN.

Hepatocyte-protective effect of nectandrin B, a nutmeg lignan, against oxidative stress: Role of Nrf2 activation through ERK phosphorylation and AMPK-dependent inhibition of GSK-3β

Oxidative stress can contribute to the development and progression of liver diseases, such as drug-induced or alcoholic liver injury, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Nectandrin B is a bioactive lignan isolated from nutmeg extract. To date, little information is available about its pharmacological activities in the liver. This study investigated the hepatocyte-protective effect of nectandrin B against tert-butylhydroperoxide-induced oxidative injury and the underlying molecular mechanism. The cell viability assay revealed that nectandrin B prevents apoptosis stimulated by tert-butylhydroperoxide in both HepG2 cells and primary mouse hepatocytes. Nectandrin B also attenuated ROS production and restored the depleted glutathione level. Real-time PCR and immunoblot analyses showed that the expression of glutamate-cysteine ligase, an enzyme responsible for the glutathione biosynthesis, was induced by nectandrin B, indicating its indirect antioxidative effect. The NF-E2-related factor-2 (Nrf2) regulates gene expression of an array of antioxidant enzymes in hepatocytes. Nectandrin B stimulated Nrf2 activation as evidenced by its enhanced nuclear accumulation and increased antioxidant response element (ARE)-luciferase activity. Intriguingly, the hepatocyte-protective effect of nectandrin B against oxidative damage was completely abrogated by Nrf2 knockdown using Nrf2 specific siRNA. Nectandrin B promoted ERK activation, but inactivated GSK-3β through the AMPK-mediated inhibitory phosphorylation. The enforced overexpression of dominant-negative mutant of MEK1 or AMPKα, or wild-type GSK-3β inhibited the increase in the NQO1-ARE-luciferase activity stimulated by nectandrin B, suggesting that both ERK and AMPK-GSK-3β signalings are involved in the activation of Nrf2/ARE pathway by nectandrin B. Consistent with this, cytoprotection and restoration of glutathione level by nectandrin B was also blocked by the overexpression of dominant-negative MEK1 or wild-type GSK-3β. Finally, our data demonstrate that nectandrin B has the ability to protect hepatocytes against oxidative injury through the activation of Nrf2/ARE pathway mediated by ERK phosphorylation and AMPK-dependent inactivation of GSK-3β.

Prevention of cyclophosphamide-induced hepatotoxicity and genotoxicity: Effect of an L-cysteine based oxovanadium(IV) complex on oxidative stress and DNA damage.

Vanadium has been emerged as a promising agent owing to its ability to prevent several types of cancer. This study was aimed to investigate the protective role of an organovanadium complex, viz., oxovanadium(IV)-L-cysteine methyl ester (VC-IV) against cyclophosphamide (CP)-induced hepatotoxicity and genotoxicity in mice. Oral administration of VC-IV quite effectively ameliorated CP-induced histopathological lesions and reduced levels of alanine transaminase, aspartate transaminase and alkaline phosphatase. In addition, VC-IV significantly attenuated CP-induced oxidative stress in the liver as evident from levels of reactive oxygen species, nitric oxide and lipid peroxidation. Restoration of glutathione level and activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase) were also observed upon VC-IV administration. Moreover, VC-IV significantly mitigated CP-induced chromosomal aberrations, micronuclei formation, DNA fragmentation and apoptosis in bone marrow cells and DNA damage in lymphocytes. The present study showed that VC-IV could provide adequate protection against CP-induced hepatotoxicity and genotoxicity in vivo.

Zinc causes acute impairment of glutathione metabolism followed by coordinated antioxidant defenses amplification in gills of brown mussels Perna perna

Zinc demonstrates protective and antioxidant properties at physiological levels, although these characteristics are not attributed at moderate or high concentrations. Zinc toxicity has been related to a number of factors, including interference with antioxidant defenses. In particular, the inhibition of glutathione reductase (GR) has been suggested as a possible mechanism for acute zinc toxicity in bivalves. The present work investigates the biochemical effects of a non-lethal zinc concentration on antioxidant-related parameters in gills of brown mussels Perna perna exposed for 21days to 2.6μM zinc chloride. After 2days of exposure, zinc caused impairment of the antioxidant system, decreasing GR activity and glutathione levels. An increase in antioxidant defenses became evident at 7 and 21days of exposure, as an increase in superoxide dismutase and glutathione peroxidase activity along with restoration of glutathione levels and GR activity. After 7 and 21days, an increase in cellular peroxides and lipid peroxidation end products were also detected, which are indicative of oxidative damage. Changes in GR activity contrasts with protein immunoblotting data, suggesting that zinc produces a long lasting inhibition of GR. Contrary to the general trend in antioxidants, levels of peroxiredoxin 6 decreased after 21days of exposure. The data presented here support the hypothesis that zinc can impair thiol homeostasis, causes an increase in lipid peroxidation and inhibits GR, imposing a pro-oxidant status, which seems to trigger homeostatic mechanisms leading to a subsequent increase on antioxidant-related defenses.

Modulation of age‐related changes in oxidative stress markers and energy status in the rat heart and hippocampus: a significant role for ozone therapy

Oxidative stress emerges as a key player in the ageing process. Controlled ozone administration is known to promote an oxidative preconditioning or adaptation to oxidative stress. The present study investigated whether prophylactic ozone administration could interfere with the age-related changes in the heart and the hippocampus of rats. Four groups of rats, aged about 3 months old, were used. Group 1 (Prophylactic ozone group) received ozone/oxygen mixture by rectal insufflations (0.6 mg/kg) twice/week for the first 3 months, then once/week till the age of 15 months. Group 2 (Oxygen group) received oxygen as vehicle for ozone in a manner similar to group 1. Group 3 (Aged control group) was kept without any treatment until the age of 15 months. A fourth group of rats (Adult control group) was evaluated at 3 months of age to provide baseline data. Ozone alleviated age-associated redox state imbalance as evidenced by reduction of lipid and protein oxidation markers, lessening of lipofuscin deposition, restoration of glutathione levels in both tissues and normalization of glutathione peroxidase activity in the heart tissue. Ozone also mitigated age-associated energy failure in the heart and the hippocampus, improved cardiac cytosolic Ca(2+) homeostasis and restored the attenuated Na(+) , K(+) -ATPase activity in the hippocampus of aged rats. These data provide new evidence concerning the anti-ageing potential of prophylactic ozone administration.

Cytoskeletal architecture regulates cyclooxygenase‐2 in human endothelial cells: Autocrine modulation by prostacyclin

Endothelium is a highly dynamic tissue that controls vascular homeostasis. This requires constant rearrangements of the shape or function of endothelial cells that cannot set aside the role of the cytoskeleton. The aim of this study was to determine the mechanisms by means of which cytoskeletal alterations induce cyclooxygenase-2 (Cox-2) expression in human endothelial cells using compounds that interfere with microtubule or actin architecture. Microtubule disruption by nocodazole markedly increased Cox-2 expression and activity, and provoked paracellular gap formation, a cardinal feature of endothelial barrier dysfunction. The Cox-2 metabolite prostacyclin down-regulated Cox-2 through an autocrine receptor-mediated mechanism, and partially prevented the disassembly of endothelial monolayers. There was also an interaction between microtubules and actin filaments in nocodazole-induced Cox-2 expression. Nocodazole provoked the dissolution of the F-actin cortical ring and stress fiber formation, increased actin glutathionylation, and concomitantly lowered intracellular levels of reduced glutathione. The restoration of glutathione levels by N-acetylcysteine opposed Cox-2 expression and preserved the integrity of endothelial monolayers. Among the signaling pathways connecting microtubule disruption with Cox-2 up-regulation, crucial roles are played by Src family kinase activation, serine/threonine phosphatase 2A inhibition, and the phosphorylation of mitogen activated protein kinase p38. Our findings provide a mechanistic insight into the observation that Cox-2 is induced in endothelial cells under cytoskeleton-perturbing conditions such as those occurring in the presence of atherogenic/inflammatory stimuli and oxidative stress. In this scenario, Cox-2 up-regulation by endothelia exposed to noxious conditions can be considered protective of the vasodilatory and anti-thrombotic properties of the vessel wall.

Hepatoprotective and Antioxidant Action of Moringa oleifera Lam.Against Acetaminophen Induced Hepatotoxicity in Rats

This study is conducted to investigate the possible hepatoprotective action of Moringa oleifera Lam. (MO), a high value medicinal plant against a single high dose of APAP induced hepatotoxicity. Male Sprague Dawley rats were dosed with APAP (3000 mg kg-1 body weight; p.o.) to induce hepatocellular damage. In rats that were pretreated with MO (200 and 800 mg kg-1, p.o.) for 14 days prior to APAP treatment there was a reduction of liver enzymes (ALT, AST and ALP) and also the restoration of glutathione level. The biochemical results showed parallel finding with the histopathological analysis in which liver sections obtained from rats pretreated with MO, the damage was blocked. Intriguingly, MO alone has significantly elevated the level glutathione compared to the control group. The findings has suggested that Moringa oleifera Lam. is a promising product in protecting the liver against APAP induced liver injury via the restoration and elevation of glutathione level in the liver.

Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level

Initiation of acetaminophen (APAP) toxicities is believed to be promoted by oxidative stress during the event of overdosage. The aim of the present study was to evaluate the hepatoprotective action of Moringa oleifera Lam (MO), an Asian plant of high medicinal value, against a single high dose of APAP. Groups of five male Sprague–Dawley rats were pre-administered with MO (200 and 800 mg/kg) prior to a single dose of APAP (3 g/kg body weight; p.o). Silymarin was used as an established hepatoprotective drug against APAP induced liver injury. The hepatoprotective activity of MO extract was observed following significant histopathological analysis and reduction of the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in groups pretreated with MO compared to those treated with APAP alone. Meanwhile, the level of glutathione (GSH) was found to be restored in MO-treated animals compared to the groups treated with APAP alone. These observations were comparable to the group pretreated with silymarin prior to APAP administration. Group that was treated with APAP alone exhibited high level of transaminases and ALP activities besides reduction in the GSH level. The histological hepatocellular deterioration was also evidenced. The results from the present study suggested that the leaves of MO can prevent hepatic injuries from APAP induced through preventing the decline of glutathione level.

Bax gene expression alters Ca(2+) signal transduction without affecting apoptosis in an epithelial cell line.

Bax is an oncogene that has proapoptotic properties but not all cells that express Bax undergo apoptosis. Bax may have a function unrelated to apoptosis. To elucidate the role of Bax in cell signaling, an epithelial cell line called SMG-C6 was transfected with the human bax gene. Stable transfectants were studied for their response to carbachol, a muscarinic receptor agonist, by measuring the increase in intracellular free Ca(2+) and Ca(2+) influx. Carbachol-mediated release of Ca(2+) from intracellular stores was significantly higher in Bax transfectants compared to control transfectants (empty vector). Ca(2+) influx was also increased in Bax transfectants. Bax had no affect on the storage operated channels. However, the concentration of Ca(2+) in the intracellular stores (i.e., mitochondria and granules) was 40-50% lower in the Bax transfectants. There was no significant difference in thapsigargin-mediated apoptosis in Bax transfectants compared to wild-type and control transfectants. Measurement of glutathione was reduced in the Bax transfectant. Restoration of glutathione levels with glutathione monoethyl ester partially normalized Ca(2+) mobilization and storage capacity in the mitochondria to control levels. This study shows that sub-apoptotic levels of Bax can reduce Ca(2+) content in intracellular stores and Ca(2+) homeostasis. Bax may mediate these effects by reducing the levels of antioxidants resulting in mild oxidative stress.

Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions

Hyperglycemia-induced oxidative stress may play a key role in the pathogenesis of diabetic vascular disease. The purpose of this study was to determine the effects of glucose on levels of glutathione (a major intracellular antioxidant), the expression of γ-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione de novo synthesis), and DNA damage in human vascular smooth muscle cells in vitro. High glucose conditions and buthionine sulphoximine, an inhibitor of γ-glutamylcysteine synthetase, reduced intracellular glutathione levels in vascular smooth muscle cells. This reduction was accompanied by a decrease in the mRNA expression of both subunits of γ-glutamylcysteine synthetase as well as an increase in DNA damage. In high glucose conditions, incubation of the vascular smooth muscle cells with α-lipoic acid and L-cystine restored glutathione levels. We suggest that the decrease in GSH levels seen in high glucose conditions is mediated by the availability of cysteine (rate-limiting substrate in de novo glutathione synthesis) and the gene expression of the γ-glutamylcysteine synthetase enzyme. Glutathione depletion is associated with an increase in DNA damage, which can be reduced when glutathione levels are restored.

Reactive oxygen species uncouple external horizontal cells in the carp retina and glutathione couples them again

We have investigated the effect of free radicals on the electrical gap junctions between horizontal cells in the carp retina. In our previous study, l-buthionine sulfoximine, an inhibitor of glutathione synthesis, caused uncoupling of horizontal cells four days after injection. In the present study, we have used paraquat, a generator of exogenous reactive oxygen species, to investigate whether it was the depletion of glutathione or an increase in the level of reactive oxygen species which resulted in horizontal cell uncoupling after l-buthionine sulfoximine injection. Intracellular recordings were made from L-type horizontal cells at various time-points after intravitreal injection of paraquat. Injection of 25 nmol paraquat caused an increase in response amplitude to central spot light stimuli by two days after injection, which continued for a further two to three days and had almost disappeared by seven days after injection. There was also a sharp increase in reactive oxygen species production, peaking at four days and disappearing by seven days after injection, and an accompanying depletion and a restoration of glutathione levels with a similar time-course. Marking cells with Lucifer Yellow clearly illustrated uncoupling of horizontal cells after paraquat injection. If paraquat and l-buthionine sulfoximine were injected simultaneously, the increase in response to central spots was observed as early as one day after injection. This response amplitude was not more enhanced than that observed after l-buthionine sulfoximine injection alone, although a dramatic increase in the level of reactive oxygen species was observed. From these results, we suggest that reactive oxygen species are involved in uncoupling, while recovery from uncoupling is dependent on glutathione. Furthermore, we conclude that a balance between glutathione and reactive oxygen species levels is the most important factor controlling gap junctional intercellular communication of L-type horizontal cells in the carp retina.

S-ADENOSYL-L-METHIONINE: ROLE IN PHOSPHATIDYLCHOLINE SYNTHESIS AND IN VITRO EFFECTS ON THE ETHANOL-INDUCED ALTERATIONS OF LIPID METABOLISM

Hepatic lipid metabolism is extremely modified by excessive ethanol consumption, but the cellular mechanisms of such alterations are still largely unexplored.S-Adenosyl-L-methionine (SAMe) is known as an important methylating agent and as a precursor of glutathione and it has been shown to prevent some of the toxic effects of ethanol in the liver. We therefore studied the effects of ethanol on cholesterol synthesis in a human hepatomal cell line (HepG2), the kinetics of SAMe, and its putative protective effects on the alterations of lipid metabolism induced by toxic concentrations of alcohol. Incubation of HepG2 cells with [3H]SAMe resulted in a progressive increase in the labelling of phosphatidylcholine and of its two intermediates during synthesis starting from phosphatidylethanolamine. This process is enzymatic, since it does not take place in heat-inactivated cells. Also, ethanol induced an increase in cholesterol and triglycerides syntheses and a decrease in phospholipid labelling. These alterations were not prevented by SAMe 10−4M, indicating that the protective effects of the drug are related to other mechanisms of action such as reduced formation of collagen, restoration of glutathione levels, and normalization of membrane functions.

S-adenosyl-L-methionine synthetase and methionine metabolism deficiencies in cirrhosis.

Methionine metabolism impairment in human liver disease has been related with an alteration in SAM-synthetase. This deficiency is produced by a post-translational event since human liver cirrhosis presents normal levels of SAM-synthetase mRNA in spite of a more than 50% diminution in its activity. A series of different experiments on the structure and activity of this enzyme have provided strong evidence that SAM-synthetase is regulated by reduced/oxidized glutathione ratio. Restoration of glutathione levels by the addition of S-adenosyl-methionine or glutathione esters in various experimental conditions (buthionine sulfoximine and carbon tetrachloride intoxication) resulted in a normalization of the SAM-synthetase diminution caused by the toxics and an attenuation of the morfological alteration produced in the liver, including fiber production. This findings might have pharmacological implications in the treatment of liver diseases, since the possible beneficial effect of long term administration of SAM could include a reduction of fiber production.

Impairment of Methionine Metabolism in Liver Disease

Methionine metabolism is impaired in patients with liver damage and this alteration might complicate and maintain the clinical syndrome. Alterations in this pathway are associated with a defect in S-adenosyl-L-methionine (SAMe) synthetase activity. Liver glutathione, which is derived from SAMe via the transsulphuration pathway, is also depleted as a result of liver damage. Glutathione appears to protect against SAMe synthetase inactivation by preventing oxidation of sulfhydryl groups; thus, its depletion further reduces SAMe synthetase activity, and a vicious circle may develop. Restoration of glutathione levels by the addition of treatment with SAMe or glutathione esters in various experimental conditions (buthionine sulfoximine and carbon tetrachloride intoxication) has resulted in attenuation of the damage produced by the toxins. Moreover, exogenously administered SAMe has been used successfully in patients with liver disease. The elucidation of the mechanisms that regulate methionine metabolism might lead to the development of new therapeutic approaches in liver disease.

Interaction of Alcohol with Other Drugs and Nutrients

Two decades of research in ethanol metabolism have culminated in the molecular elucidation of an ethanol-inducible cytochrome P450 (P450IIE1) which is not only involved with ethanol metabolism and ethanol tolerance, but also with the activation of a number of xenobiotics. The unique ability of P450IIE1 to activate xenobiotic agents now appears to be responsible for the increased susceptibility of the heavy drinker to hepatotoxic industrial solvents, commonly used drugs, over-the-counter medications and chemical carcinogens. It also explains some of the interaction of ethanol with nutritional factors, such as hepatic vitamin A: enhanced microsomal degradation of retinoids (together with hepatic mobilisation) promotes depletion. Treatment, however, is complicated by the fact that ethanol also enhances the toxicity of excess vitamin A. All pathways of ethanol metabolism result in the production of acetaldehyde, the toxicity of which has been reviewed (Lieber 1982). New aspects discussed here include the formation of acetaldehyde-protein adducts and an associated immune response that may play a pathogenic role. Also discussed are the implications of ethanol-induced alterations in microtubules, mitochondria and plasma membranes, as they relate, in part, to accompanying acetaldehyde-induced toxicity, to the production of free radicals or to lipid peroxidation-mediated injury associated with glutathione depletion. There is also depletion of S-adenosyl-L-methionine (SAMe). Administration of synthetic SAMe results in a partial correction of the SAMe depletion and a consequent restoration of glutathione levels. Other beneficial effects of SAMe include a significant attenuation of the increase in plasma aspartate transaminase and glutamate dehydrogenase activities. Mitochondrial damage, including giant forms, documented by light and electron microscopy, is also attenuated by SAMe. Thus, the new understanding of the pathophysiology of alcohol-induced liver damage has led to more successful therapy with drugs and nutritional factors.