Lipid Peroxidation, CYP2E1 and Arachidonic Acid Metabolism in Alcoholic Liver Disease in Rats

French, Samuel W.; Morimoto, Michio; Reitz, Ronald C.; Koop, Dennis R.; Klopfenstein, Bethany J.; Estes, Karen C; Clot, Paolo; Ingelman‐Sundberg, Magnus; Albano, E.

doi:10.1093/jn/127.5.907s

Cited by 91 publications

(54 citation statements)

References 21 publications

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“…Note that CYP4F3B was also identified as the enzyme producing 20-HETE in HepaRG cells (Antoun et al, 2008). This functional feature of HepaRG cells offers new clues to highlight the mechanisms of toxicity induced by FA derivatives described as toxic metabolites in mammals but also by epoxyeicosatrienoic acids, found to accumulate in alcoholic liver disease in rat (French et al, 1997).…”

Section: Steps Of Differentiationmentioning

confidence: 74%

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

Madec¹,

Cérec²,

Plée-Gautier³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Fatty acid microsomal -oxidation involves cytochrome P450 enzymes. Some of them belonging to the CYP4F3 family are mainly expressed in the liver, making this organ a major player in energy homeostasis and lipid metabolism. To study this important regulation pathway, we used HepaRG cells, which gradually undergo a complete differentiation process. Even at the early stage of the differentiation process, CYP4F3B generated by alternative splicing of the CYP4F3 gene represented the prevalent isoform in HepaRG cells as in the liver. Its increasing expression associated with hepatocyte differentiation status suggested a hepatic-specific control of this isoform. As in liver microsomes, the catalytic hydroxylation of the CYP4F3B substrate [1-

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Section: Steps Of Differentiationmentioning

confidence: 74%

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

Madec¹,

Cérec²,

Plée-Gautier³

et al. 2011

Drug Metab Dispos

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“…In these models, large increases in microsomal lipid peroxidation have been observed and the ethanol-induced liver pathology has been shown to correlate with CYP2E1 levels and elevated lipid peroxidation [16,63,65,76]. Experimentally, a decrease in CYP2E1 induction was found to be associated with a reduction in alcohol-induced liver injury [25,37]. CYP2E1 inhibitors such as diallyl sulfide (DAS) [62], phenethyl isothiocyanate (PIC) [4,64] and chlormethiazole [28], blocked the lipid peroxidation and ameliorated the pathologic changes in ethanol-fed rats.…”

Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

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

Cederbaum

2009

Genes Nutr

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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...

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“…In these models, large increases in microsomal lipid peroxidation have been observed and the ethanol-induced liver pathology has been shown to correlate with CYP2E1 levels and elevated lipid peroxidation (29,30,119,120). Experimentally, a decrease in CYP2E1 induction was found to be associated with a reduction in alcohol-induced liver injury (121,122). CYP2E1 inhibitors such as diallyl sulfide (DAS) (123), phenethyl isothiocyanate (PIC) (124,125) and chlormethiazole (126), blocked the lipid peroxidation and ameliorated the pathologic changes in ethanol-fed rats.…”

Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

659

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Lipid Peroxidation, CYP2E1 and Arachidonic Acid Metabolism in Alcoholic Liver Disease in Rats

Cited by 91 publications

References 21 publications

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

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

CYP2E1 and oxidative liver injury by alcohol

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