Glutathione in liver diseases and hepatotoxicity.

Yuan L, Kaplowitz N.
Internal Medicine, University of Southern California, USA; Los Angeles County (LAC) Medical Center Los Angeles, CA 90033, USA.

Glutathione (GSH) is a major antioxidant as well as redox and cell signaling regulator. GSH guards cells against oxidative injury by reducing H(2)O(2) and scavenging reactive oxygen and nitrogen radicals. In addition, GSH-induced redox shift with or without ROS subjects some cellular proteins to varied forms of oxidation, altering the function of signal transduction and transcription factor molecules. Increasing evidence supports the important role of ROS and GSH in modulating multiple signaling pathways. TNF-alpha and Fas signaling, NF-kappaB, JNK and mitochondrial apoptotic pathways are the focus of this review. The redox regulation either can switch on/off or regulate the threshold for some crucial events in these pathways. Notably, mitochondrial GSH depletion induces increased mitochondrial ROS exposure which impairs bioenergetics and promotes mitochondrial permeability transition pore opening which is critical for cell death. Depending on the extent of mitochondrial damage, NF-kappaB inhibition and JNK activation, hepatocytes may either undergo different modes of cell death (apoptosis or necrosis) or be sensitized to cell-death stimuli (i.e. TNF-alpha). These processes have been implicated in the pathogenesis of many liver diseases.

PMID: 18786561 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/18786561?dopt=AbstractPlus

Chandrasekaran VR, Wan CH, Liu LL, Hsu DZ, Liu MY.

Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.

Shock. 2008 Aug;30(2):217-21.

Acetaminophen (APAP) overdose causes acute liver injury or even death in both humans and experimental animals. We investigated the effect of sesame oil on APAP-induced acute liver injury. Male Wistar rats were given APAP (1,000 mg/kg; orally) to induce acute liver injury. Acetaminophen significantly increased aspartate transaminase, alanine transaminase, lipid peroxidation, and superoxide anion and hydroxyl radical generation levels; it also induced glutathione depletion. Sesame oil (8 mL/kg; orally) did not alter the gastric absorption of APAP, but it inhibited all the parameters altered by APAP and protected the rats against APAP-induced acute liver injury. We hypothesize that sesame oil maintained the intracellular glutathione levels, reduced reactive oxygen species levels, and inhibited lipid peroxidation in rats with APAP-induced acute liver injury.

http://www.ncbi.nlm.nih.gov/pubmed/18091569?dopt=AbstractPlus

Anti-oxidant and anti-atherogenic properties of liposomal glutathione: studies in vitro, and in the atherosclerotic apolipoprotein E-deficient mice.
Rosenblat M, Volkova N, Coleman R, Aviram M.

The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa 31096, Israel.

Liposomal glutathione, but not the control liposomes (with no glutathione), dose-dependently inhibited copper ion-induced low density lipoprotein (LDL) and HDL oxidation. As peroxidase activity was found to be present in both LDL and HDL, it has contributed to the anti-oxidative effects of liposomal glutathione. In-vitro, no significant effect of liposomal glutathione on J774 A.1 macrophage cell-line oxidative stress and on cellular cholesterol metabolism was observed. In contrast, in the atherosclerotic apolipoprotein E-deficient (E(0)) mice, consumption of liposomal glutathione (12.5 or 50mg/kg/day, for 2 months), but not control liposomes, resulted in a significant reduction in the serum susceptibility to AAPH-induced oxidation by 33%. Liposomal glutathione (50mg/kg/day) consumption also resulted in an increment (by 12%) in the mice peritoneal macrophages (MPM) glutathione content, paralleled by a significant reduction in total cellular lipid peroxides content (by 40%), compared to placebo-treated mice MPM. MPM paraoxonase 2 activity was significantly increased by 27% and by 121%, after liposomal glutathione consumption (12.5 or 50mg/kg/day, respectively). Analyses of cellular cholesterol fluxes revealed that, liposomal glutathione (12.5mg/kg/day) consumption, decreased the extent of oxidized-LDL (Ox-LDL) uptake by 17% and the cellular cholesterol biosynthesis rate, by 34%, and stimulated HDL-induced macrophage cholesterol efflux, by 19%. Most important, a significant reduction in macrophage cholesterol mass (by 24%), and in the atherosclerotic lesion area (by 30%) was noted. We thus conclude that liposomal glutathione possesses anti-oxidative and anti-atherogenic properties towards lipoproteins and macrophages, leading to attenuation of atherosclerosis development.

PMID: 17588583 [PubMed - indexed for MEDLINE]

A mathematical model of glutathione metabolism.
Reed MC, Thomas RL, Pavisic J, James SJ, Ulrich CM, Nijhout HF.

ABSTRACT: BACKGROUND: Glutathione (GSH) plays an important role in anti-oxidant defense and detoxification reactions. It is primarily synthesized in the liver by the transulfuration pathway and exported to provide precursors for in situ GSH synthesis by other tissues. Deficits in glutathione have been implicated in aging and a host of diseases including Alzheimeras disease, Parkinsonas disease, cardiovascular disease, cancer, Down syndrome and autism. Approach: We explore the properties of glutathione metabolism in the liver by experimenting with a mathematical model of one-carbon metabolism, the transsulfuration pathway, and glutathione synthesis, transport, and breakdown. The model is based on known properties of the enzymes and the regulation of those enzymes by oxidative stress. We explore the regulation of glutathione synthesis and its sensitivity to fluctuations in amino acid input. We use the model to simulate the metabolic profiles previously observed in Down syndrome and autism and compare the model results to clinical data. CONCLUSIONS: We show that the glutathione pools in hepatic cells and in the blood are quite insensitive to fluctuations in amino acid input and offer an explanation based on model predictions. In contrast, we show that hepatic glutathione pools are highly sensitive to the level of oxidative stress. The model shows that trisomy 21, an increase in oxidative stress, and subsequent increased transport of GSH precursors by peripheral cells can explain the metabolic profile of Down syndrome. The model also correctly simulates the metabolic profile of autism when oxidative stress is substantially increased, the adenosine concentration is raised, and the uptake of GSH precursors by peripheral tissues is increased. Finally, we discuss how individual variation arises and its consequences for one-carbon and glutathione metabolism.

PMID: 18442411 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/18442411?ordinalpos=22&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Prousky J.

The Canadian College of Naturopathic Medicine, 1255 Sheppard Avenue East, Toronto, ON M2K 1E2, Canada and International Primary Health Care, The External Program, University of London, London, UK.

Evid Based Complement Alternat Med. 2008 Mar;5(1):27-35.

Reduced glutathione or simply glutathione (gamma-glutamylcysteinylglycine; GSH) is found in the cytosol of most cells of the body. GSH in the epithelial lining fluid (ELF) of the lower respiratory tract is thought to be the first line of defense against oxidative stress. Inhalation (nebulized or aerosolized) is the only known method that increases GSH’s levels in the ELF. A review of the literature was conducted to examine the clinical effectiveness of inhaled GSH as a treatment for various pulmonary diseases and respiratory-related conditions. This report also discusses clinical and theoretical indications for GSH inhalation, potential concerns with this treatment, its presumed mechanisms of action, optimal doses to be administered and other important details. Reasons for inhaled GSH’s effectiveness include its role as a potent antioxidant, and possibly improved oxygenation and host defenses. Theoretical uses of this treatment include Farmer’s lung, pre- and postexercise, multiple
chemical sensitivity disorder and cigarette smoking. GSH inhalation should not be used as a treatment for primary lung cancer. Testing for sulfites in the urine is recommended prior to GSH inhalation.
Minor side effects such as transient coughing and an unpleasant odor are common with this treatment. Major side effects such as bronchoconstriction have only occurred among asthma patients presumed
to be sulfite-sensitive. The potential applications of inhaled GSH are numerous when one considers just how many pulmonary diseases and respiratory-related conditions are affected by deficient antioxidant status or an over production of oxidants, poor oxygenation and/or impaired host defenses. More studies are clearly warranted.

http://www.ncbi.nlm.nih.gov/pubmed/18317545?dopt=AbstractPlus

PMID: 18317545 [PubMed - in process]