CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction

Abstract

The mechanisms by which alcohol causes cell injury are not clear. A major mechanism that is the focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol-elevated production of lipopolysaccharide (LPS) and TNFa and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other, however, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNF toxicity and that oxidants, such as peroxynitrite, activation of p38 and JNK MAP kinases, inactivation of NF-kB protective pathways and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNF potentiated hepatotoxicity. This review will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved.Keywords Alcohol Á CYP2E1 Á Lipopolysaccharide Á Oxidative stress Á Tumor necrosis factor alpha Alcohol, oxidative stress and cell injuryThe ability of acute and chronic ethanol treatment to increase production of reactive oxygen species and to enhance peroxidation of lipids, protein, and DNA has been demonstrated in a variety of systems, cells, and species, including humans [3]. Despite a tremendous growth in understanding alcohol metabolism and actions, the mechanism(s) by which alcohol causes cell injury are still not clear. A variety of leading mechanisms has been briefly summarized [13,17,67], and it is likely that many of them ultimately converge as they reflect a spectrum of the organism's response to the myriad of direct and indirect actions of alcohol. A major mechanism that is a focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a key role in how ethanol induces ''oxidative stress''. Some of these include redox state changes (decrease in the NAD ? /NADH redox ratio) produced as a result of ethanol oxidation by alcohol and aldehyde dehydrogenases; production of the reactive product acetaldehyde as a consequence of ethanol oxidation by all major oxidative pathways; damage to mitochondria which results in decreased ATP production; direct or membrane effects caused by hydrophobic ethanol interaction with either phospholipids or protein components or enzymes; ethanol-induced hypoxia, especially in the pericentral zone of the liver acinus as oxygen is consumed in order for the liver to detoxify ethanol via oxidation; ethanol effects on the immune system, and altered cytokine production; ethanol-induced increase in bacterialderived endotoxin with subsequent activation of Kupffer cells; ethanol induction of CYP2E1; ethanol mobilization of iron which results in enhanced levels of low molecular weight non-heme iron; effects...

Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances

“…CYP2E1 is indeed suggested to induce its damaging effects to the liver following ethanol exposure due to its ability to produce oxidative radicals such as hydrogen peroxide and superoxide anion. There are several mechanisms by which elevated CYP2E1 exerts its pathological effects through increasing nitroxidative stress and lipid peroxidation, which stimulates inflammatory response and production of pro-inflammatory cytokines through activation of a redox-sensitive transcription factor nuclear factor kappa-B (NF-κB) and others [44, 67–69]. The oxidative stress-mediated hepatic injury has been largely attributed to direct damage by oxidative radicals to mitochondrial DNA and/or PTMs of many mitochondrial proteins, which will be discussed in the following sections.…”

Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

“…In addition to increased liver ROS production, both LPS and INH amplifies CYP2E1 production, which in returns exaggerates their tissue damage capabilities (Lu and Cederbaum, 2010; Aubert et al, 2011; Cederbaum et al, 2012). …”

Effect of Ambroxol and Beclomethasone on Lipopolysaccharide-Induced Nitrosative Stress in Bronchial Epithelial Cells

“…The interaction between nitrosative stress and the activation of the p38 MAPK pathway is a well-defined pathological mechanism in inflammatory disease [53,54,55], and the capability of ambroxol to prevent p38 phosphorylation, as shown in ours and in a previous study [56], suggests that this drug is able to inhibit the p38 MAPK signalling pathway in relation to nitrosative stress. Moreover, LPS inhalation in human volunteers induced activation of bronchial epithelium by increased expression of p38 MAPK and IL-8 [57], and the addition of p38 MAPK inhibitors reduced IL-8 expression in BEAS-2B stimulated by flagellin from P. aeruginosa [58], indicating that p38 inhibition might have a relevant role in reducing LPS-induced epithelial-cell-derived inflammation.…”