The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model

Butura, Angelica; Nilsson, Karolina; Morgan, Kengathevy; Morgan, Timothy R.; French, Samuel W.; Johansson, Inger; Schuppe-Koistinen, Ina; Ingelman‐Sundberg, Magnus

doi:10.1016/j.jhep.2008.10.020

Cited by 101 publications

(92 citation statements)

References 47 publications

(56 reference statements)

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“…Recent work has shown that CYP2E1 activity correlates with ethanol-induced liver injury, lipid peroxidation, and collagen deposition [132] . CYP2E1 deletion effectively blocks ethanol-mediated lipid peroxidation and reduces liver injury, as shown in CYP2E -/-mice [133] . In contrast, transgenic mice overexpressing CYP2E1 [134] enhance oxidant stress and hepatic fibrogenesis.…”

Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 79%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

403

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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Section: Mechanism Of Alcohol-induced Fibrogenesismentioning

confidence: 79%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

403

339

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“…Moreover, the TLE-downregulated CYP2E1 expression may result in reduced CYP2E1 enzyme, which is involved in the metabolic activation of many toxic compounds such as ethanol (Butura et al, 2009), carbon tetrachloride (Takahashi et al, 2002), and acetaminophen (Kim et al, 2007). The ability of acute and chronic ethanol consumption to increase CYP2E1 activity is related to the production of ROS, and enhanced oxidation of lipids, proteins, and DNA have been reported (Butura et al, 2009). Diabetes induced the expression of CYP2E1 mRNA and protein levels several fold (Woodcroft et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Thunbergia laurifolia extract minimizes the adverse effects of toxicants by regulating P-glycoprotein activity, CYP450, and lipid metabolism gene expression in HepG2 cells

2014

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ABSTRACT. Thunbergia laurifolia (TL) is widely used as an antidote in Thai traditional medicine against toxic substances such as alcohol, pesticides, arsenic, and strychnine. We found that the lyophilized form of TL in 80% ethanol possessed the antioxidant levels within the range 23,163.9 ± 1457.4 Trolox equivalents mM/kg dry mass and 899.8 ± 14.5 gallic acid equivalents mM/kg dry mass using the oxygen radical absorbance capacity assay and the Folin Ciocalteu phenol assay, respectively. TL extract (TLE) at a high dose (3000 mg/L) induced cytotoxicity according to the neutral red assay and the MTT assay. However, TLE doses of 800-3000 mg/L could reduce intracellular oxidative stress in a dose-dependent manner (P < 0.05) using the dichlorodihydrofluorescein diacetate assay. TLE significantly enhanced the mRNA expression of CYP1A1, CYP1A2, CYP2B6, CYP3A4, and PPARg, but it significantly inhibited the mRNA expression of CYP3A7, CYP2D6, and CYP2E1 (P < 0.05) by reverse transcription-polymerase chain reaction. Moreover, TLE could increase the activity of a multidrug transporter, P-glycoprotein, which accelerated the excretion of toxic substances from HepG2 cells. It is suggested that TLE may be beneficial for detoxification by reducing oxidative stress, minimizing toxicity by regulating the expression CYP450 mRNAs for suitable production of CYP450 isoenzymes, and increasing PPARg mRNA expression and P-glycoprotein activity in HepG2 cells, thereby maintaining xenobiotic biotransformation balance.

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“…[13][14][15][16][17][18] The overexpression of CYP2E1 is associated with several cellular markers of oxidative stress, as well as with decreased viability as a result of both necrosis and apoptosis. [19][20][21][22] Oxidative stress and apoptosis in myocytes play important roles in the pathogenesis of cardiovascular diseases, such as ischemic heart disease, atherosclerosis, cardiomyopathy, and heart failure. [23][24][25][26][27][28] We hypothesized that CYP2E1 is an important gene in the pathogenesis of DCM and that knockdown of CYP2E1 would inhibit oxidative stress and apoptosis of myocytes, thereby preventing the development of DCM.…”

mentioning

confidence: 99%

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

Zhang

et al. 2012

Hypertension

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Abstract-Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT R141W and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of ␣-myosin heavy chain (MHC)-cTnT R141W ϫCYP2E1-silence double-transgenic mice when compared with the cTnT R141W transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT R141W transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT R141W or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.

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The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model

Cited by 101 publications

References 47 publications

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Thunbergia laurifolia extract minimizes the adverse effects of toxicants by regulating P-glycoprotein activity, CYP450, and lipid metabolism gene expression in HepG2 cells

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice

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The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model

Cited by 101 publications

References 47 publications

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Thunbergia laurifolia extract minimizes the adverse effects of toxicants by regulating P-glycoprotein activity, CYP450, and lipid metabolism gene expression in HepG2 cells

Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT R141W Dilated Cardiomyopathy Transgenic Mice

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Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT ^R141W Dilated Cardiomyopathy Transgenic Mice