Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis

Morimoto, Michio; Hagbjörk, A. L.; Nanji, Amin A.; Ingelman‐Sundberg, Magnus; Lindros, Kai O.; Fu, Paul; Albano, Emanuele; French, Samuel W.

doi:10.1016/0741-8329(93)90065-v

Cited by 152 publications

(85 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Induction of CYP2E1 in alcohol-fed animals has been shown to increase the lipid peroxidation of hepatic microsomes. 41,42 A previous study 33 reported on the up-regulation of ␥-glutamylcysteine synthetase and of increased GSH levels in CYP2E1-expressing HepG2 cells. In the present study, overexpression of CYP2E1 in HepG2 cells was found to induce expression of catalase and alpha and microsomal GST, and this induction confers at least some resistance to the cells against several prooxidants.…”

Section: Discussionmentioning

confidence: 99%

Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress

2001

View full text Add to dashboard Cite

Induction of cytochrome P450 2E1 (CYP2E1) and the formation of reactive oxygen species (ROS) appear to be one of the mechanisms by which ethanol is hepatotoxic. Glutathione peroxidase and catalase detoxify H 2 O 2 . Glutathione Stransferases (GST) provide protection from membrane lipid peroxidation, have GSH peroxidase activity, and reduce lipid hydroperoxides. Previous studies showed an up-regulation of GSH synthesis in CYP2E1 expressing HepG2 cells; this finding prompted an evaluation of the levels of other antioxidant exzymes. In CYP2E1 expressing cells, the alpha and microsomal GST messenger RNA (mRNA) are increased by 4-and 2-fold, respectively, and catalase protein and mRNA is increased by 2-fold. The increase in alpha and microsomal GST mRNA correlates with increased total enzymatic activity and is caused by increased transcription as evidenced by run-on transcription assays. In HepG2 cells transfected to express a different cytochrome P450, CYP3A4, there was an increase in alpha GST. However, in contrast to the CYP2E1 expressing cells, neither microsomal GST nor catalase were induced, suggesting some specificity for CYP2E1. In agreement with an increased antioxidant defense system, the sensitivity to added prooxidants such as menadione, antimycin A, H 2 O 2 , and 4-hydroxynonenal was lower in the CYP2E1 expressing cells as compared with control cells. In conclusion, overexpression of CYP2E1 in HepG2 cells, besides elevating total GSH levels, also induces expression of catalase and alpha and microsomal GST. This induction confers resistance to the cells against several prooxidants and is suggested to reflect an adaptive response by the cells against CYP2E1-mediated oxidative stress. (HEPATOLOGY 2001;33:652-661.)The glutathione S-transferases (GST; EC 2.5.1.18) are a family of enzymes that catalyze the conjugation of glutathione (GSH) to a wide variety of hydrophobic molecules of both exogenous and endogenous origin. 1-3 The cytosolic GSTs are dimeric proteins of subunits having a molecular mass in the 22-to 28-kd range. On the basis of their amino acid sequence, 5 classes have been described, namely alpha, mu, pi, theta, and sigma. [4][5][6] In humans the alpha class, subunits A1 and A2, is the predominant GST accounting for about 85% of the total GST protein. The major GST subunits expressed in rat liver are the alpha class, subunits A1 and A2, and the mu class, subunits 3 and 4, 7,8 whereas most of the cytosolic GST in HepG2 cells is the alpha isozyme. 9 ␣,␤, unsaturated aldehydes, such as 4-hydroxy-2,3-nonenal (4-HNE) and other endogenous or exogenous aldehydes, are generated in response to a variety of oxidative stimuli such as free intracellular iron, 10 chronic ethanol consumption, 11,12 and treatment with anticancer drugs. 13 GST-mediated conjugation of 4-HNE to GSH is the major pathway for 4-HNE metabolism. 14,15 Among the numerous cytosolic GST isozymes, the alpha-class displays the highest activity toward lipid hydroperoxides and has been implicated in the protection against oxidative stress. [1...

show abstract

Section: Discussionmentioning

confidence: 99%

Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress

2001

View full text Add to dashboard Cite

show abstract

“…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. Polyenylphosphatidylcholine (PPC), another compound exerting anti-CYP2E1 properties (127) was effective in opposing alcohol-induced oxidative stress (40).…”

Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

662

534

View full text Add to dashboard Cite

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.

show abstract

“…Large fatty droplets and pendent on the type of dietary fat with the highest levels inflammatory cells could be seen clearly in the liver of the occurring in rats fed fish oil and ethanol. 25,38,39 Thus, the ethanol-fed rat (Fig. 5A-C) but not in the rat fed isocaloric higher serum acetaldehyde concentrations and increased levdextrose (Fig.…”

Section: Modified Proteins In the Livers Of Rats Fed Fish Oil With Ormentioning

confidence: 99%

Acetaldehyde-modified and 4-hydroxynonenal-modified proteins in the livers of rats with alcoholic liver disease

Nanji

Siakotos

et al. 1997

Hepatology

View full text Add to dashboard Cite

modification by acetaldehyde correlates well with the severity Liver proteins form adducts with acetaldehyde and are of liver injury in ethanol-fed rats, whereas modification by modified by products of lipid peroxidation in alcohol-fed anithe lipid peroxidation product 4-HNE shows no correlation mals. It has been hypothesized that the formation of these with the severity of liver injury. (HEPATOLOGY 1997;26:650-modified liver proteins may contribute to liver injury in alco-657.) holic liver disease. The present work was performed to determine the extent of protein modification in rats with experimental alcoholic liver disease. Rats were fed ethanolThe major pathway for ethanol disposition involves alcointragastrically with medium chain triglycerides (MCTs), hol dehydrogenase, an enzyme that catalyzes the conversion palm oil, corn oil, or fish oil. The group fed MCTs and ethanol of ethanol to acetaldehyde. 1 With prolonged alcohol conshowed no liver injury, rats fed palm oil and ethanol showed sumption, the metabolic pathway through cytochrome P450 only fatty liver, rats fed corn oil and ethanol showed fatty 2E1 becomes important. 2 Both alcohol dehydrogenase and liver with moderate necrosis and inflammation, and rats fed cytochrome P450 2E1 generate acetaldehyde from ethanol. 1,2 fish oil and ethanol showed fatty liver with severe necrosisIn recent years, extensive evidence supporting a role for acetand inflammation. Antibodies were raised by using keyhole aldehyde in the detrimental actions of ethanol on the liver limpet hemocyanin modified in vitro by 4-hydroxynonenal (4-has been accumulated. 3 One basis of the toxic effect of acetal-HNE) or acetaldehyde as immunogens. When liver extracts dehyde is the covalent binding of this highly reactive chemiwere examined by Western blot analysis, the intensities of the cal to proteins. 4 Although the adduct formation between acetacetaldehyde-modified protein band (37 kd) in the alcohol-fed aldehyde and hepatic proteins has been well established, 5-11 animals were significantly different among the ethanol-treated its precise role in causing liver injury remains unclear. We groups and correlated with plasma acetaldehyde concentrahave previously detected a protein-acetaldehyde adduct tions. It was strongest in rats fed fish oil and ethanol, followed (PAA) in the livers of rats fed ethanol with both low-and by rats fed palm oil and ethanol and rats fed corn oil and high-fat diets. 5,12 The 37-kd liver protein that forms acetaldeethanol, whereas rats fed MCTs and ethanol showed the hyde adduct in vivo has been identified recently as D 4 -3-weakest intensity. The 37-kd protein-adetaldehyde adduct ketosteroid-5b reductase, 13 a key enzyme involved in bile was located mainly in the pericentral region of the liver. No acid syntheses. acetaldehyde adduct was detected in the control rats that were Another area of investigation in which adduct formation pair-fed with isocaloric amounts of dextrose. Western blot has been proposed to be of pathogenic importance to alcoanalysis using ...

show abstract

Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis

Cited by 152 publications

References 16 publications

Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress

Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress

CYP2E1 and oxidative liver injury by alcohol

Acetaldehyde-modified and 4-hydroxynonenal-modified proteins in the livers of rats with alcoholic liver disease

Contact Info

Product

Resources

About