Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Oz, Helieh S.; Im, Hee-Jeong; Chen, Theresa S.; Villiers, Willem J.S. de; McClain, Craig J.

doi:10.1002/jbt.20109

Cited by 67 publications

(64 citation statements)

References 30 publications

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“…The results of our studies suggest that diet, including anti-oxidant supplements and maintenance of cellular GSH levels, may be important in preventing the development of chronic non-alcoholic liver disease (CNLD), non-alcoholic steatohepatitis, and hepatocellular carcinoma. The importance of such protection was recently emphasized by a report showing that glutathione-enhancing agents provided protection against steatohepatitis in a rat dietary model of this disease (Oz et al, 2006). Our studies implicate insulin signaling pathways involving PI3K and its downstream effectors in the insulin-mediated regulation of drug metabolizing enzymes including CYP2E1, alpha-class GSTs, mEH and GCL catalytic subunit.…”

Section: Resultsmentioning

confidence: 54%

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The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Kim

Novak

2007

Pharmacology & Therapeutics

142

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Endogenous factors, including hormones, growth factors and cytokines, play an important role in the regulation of hepatic drug metabolizing enzyme expression in both physiological and pathophysiological conditions. Alterations of hepatic drug metabolizing enzymes gene and protein expression, observed in diabetes, fasting, obesity, protein-calorie malnutrition and long-term alcohol consumption alters the metabolism of xenobiotics, including procarcinogens, carcinogens, toxicants, and therapeutic agents and may also impact the efficacy and safety of therapeutic agents, as well as result in drug-drug interactions. Although the mechanisms by which xenobiotics regulate drug metabolizing enzymes have been studied intensively, less is known regarding the cellular signaling pathways and components which regulate drug metabolizing enzyme gene and protein expression in response to hormones and cytokines. Recent findings, however, have revealed that several cellular signaling pathways are involved in hormone-and growth factor-mediated regulation of drug metabolizing enzymes. Our laboratory, and others, have demonstrated that insulin and growth factors regulate drug metabolizing enzyme gene and protein expression, including cytochromes P450, glutathione S-transferases and microsomal epoxide hydrolase, through receptors which are members of the large receptor tyrosine kinase family, and by downstream effectors such as phosphatidylinositol 3-kinase, the mitogen activated protein kinase, Akt/protein kinase B, mTOR, and the p70S6 kinase. Here, we review current knowledge of the signaling pathways implicated in regulation of drug metabolizing enzyme gene and protein expression in response to insulin and growth factors, with the goal of increasing our understanding of how chronic disease affects these signaling pathways, components, and ultimately gene expression and translational control.

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Section: Resultsmentioning

confidence: 54%

“…Reprinted from Kim SK, Abdelmegeed MA and Novak RF, J Pharmacol Exp Ther. 316, 1255-1261, 2006, with permission. Insulin effect on GCLC protein (A), GCLC mRNA (B), GCL activity (C), and GSH (D) levels in primary cultured rat hepatocytes.…”

Section: Figmentioning

confidence: 99%

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Kim

Novak

2007

Pharmacology & Therapeutics

142

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“…Similarly, oral administration of PTCA provided protection against steatohepatitis by attenuating the expression of deleterious proinflammatory and fibrogenic genes in a dietary rat model. 31 Other studies showed that PTCA significantly increased GSH biosynthesis in cultured rat lens compared with untreated controls 32 and prevented naphthalene-induced experimental cataracts in mice. 33 In this study, PTCA-treated mice had significantly normalized levels of inflammatory cytokines (IL-6 and IL-12), acute protein SAA, colon lesions, with higher levels of blood and hepatic GSH, and lower GSSG concentrations compared with other treated and untreated DSS animals.…”

Section: Discussionmentioning

confidence: 96%

Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model

Oz¹,

Chen²,

Nagasawa³

2007

Translational Research

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Oxidant-mediated injury plays an important role in the pathophysiology of inflammatory bowel disease (IBD). Recently, antioxidants were shown to modulate colitis in mice. In this study, the protective effects of L-cysteine and glutathione (GSH) prodrugs are further evaluated against progression of colitis in a murine model. ICR mice were fed compounds incorporated into chow as follows: Group (A) received chow supplemented with vehicle. Group (B) was provided 2-(RS)-npropylthiazolidine-4(R)-carboxylic-acid (PTCA), a cysteine prodrug. Group (C) received D-ribose-L-cysteine (RibCys), another cysteine prodrug that releases L-cysteine. Group (D) was fed Lcysteine-glutathione mixed sulfide (CySSG), a ubiquitous GSH derivative present in mammalian cells. After 3 days, the animals were further provided with normal drinking water or water supplemented with dextran sodium sulfate (DSS). Mice administered DSS developed severe colitis and suffered weight loss. Colonic lesions significantly improved in animals treated with PTCA and RibCys and, to a lesser extent, with CySSG therapy. Hepatic GSH levels were depleted in colitis animals (control vs DSS, P < 0.001), and normalized with prodrug therapies (control vs treatments, P > 0.05). Protein expressions of serum amyloid A and inflammatory cytokines [interleukin (IL)-6, IL-12, tumor necrosis factor-alpha (TNF-α), osteopontin (OPN)] were significantly increased in colitis animals and improved with therapies. Immunohistochemistry and Western blot analyses showed significant upregulation of the macrophage-specific markers, COX-2 and CD68, which suggests macrophage activation and infiltration in the colonic lamina propria in colitis animals. These abnormalities were attenuated in prodrug-treated mice. In conclusion, these data strongly support the novel action of the PTCA against colitis, which further supports a possible therapeutic application for IBD patients.Inflamed gut from ulcerative colitis and Crohn's disease patients is rich in activated macrophages and neutrophils. These inflammatory cells generate excess amounts of reactive oxygen species (ROS) with subsequent increased oxidative stress. 1 The increased generation of highly toxic ROS exceeds the limited intestinal antioxidant defense system, thereby contributing to intestinal oxidative injury in ulcerative colitis patients. 2 Excessive production of ROS has been demonstrated in circulating phagocytic and polymorphonu-clear leukocytes cells in inflammatory bowel disease (IBD) patients, using a chemiluminescence assay 3 and after stimulation with the bacterial chemotactic peptide, N-formyl-methionyl-leucylphenylalanine. 4 Thus, oxidant-mediated injury plays an important role in the pathophysiology of IBD. The endogenous tripeptide, glutathione (GSH), is the most important intracellular defense agent in mammalian organs, including the gut. GSH is involved in protein folding and protein synthesis as well as in intracellular signaling. 5 GSH may be depleted during inflammatory insults, and GSH-deficient mice show s...

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“…In addition, two glutathione-replenishing agents, S-adenosylmethionine and 2(RS)-npropylthiazolidine-4(R)-carboxylic acid (i.e. an L-cysteine pro-drug), were shown to protect against steatohepatitis induced by the methionine-choline deficient diet; however, these agents did not prevent alterations in GSH and GSSG levels in response to steatohepatitis [88]. Nonetheless, increased GSSG concentrations were found in the blood of NASH patients suggesting defects in glutathione metabolism [89].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

381

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Cited by 67 publications

References 30 publications

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

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