High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis.

Obesity is linked to nonalcoholic steatohepatitis. Peroxisome proliferator-activated receptor-α (PPARα) regulates lipid metabolism. Cytochrome -450 2A5 (CYP2A5) is a potential antioxidant and CYP2A5 induction by ethanol is CYP2E1 dependent.

Suppressed hepatocyte proliferation via a ROS-HNE-P21 pathway is associated with nicotine- and cotinine-enhanced alcoholic fatty liver in mice.

CYP2A5 is a major enzyme responsible for nicotine and cotinine metabolism in mice. Nicotine and cotinine enhance alcoholic fatty liver in wild type (WT) mice but not in CYP2A5 knockout (KO) mice, and reactive oxygen species (ROS) generated during the CYP2A5-mediated metabolism contributes to the enhancing effect. In combination with ethanol, nicotine and cotinine increased lipid peroxidation end product 4-hydroxynonenal (HNE) in WT mice but not in KO mice.

Nicotine enhances alcoholic fatty liver in mice: Role of CYP2A5.

Tobacco and alcohol are often co-abused. Nicotine can enhance alcoholic fatty liver, and CYP2A6 (CYP2A5 in mice), a major metabolism enzyme for nicotine, can be induced by alcohol. CYP2A5 knockout (cyp2a5) mice and their littermates (cyp2a5) were used to test whether CYP2A5 has an effect on nicotine-enhanced alcoholic fatty liver.

Cytochrome P450s and Alcoholic Liver Disease.

Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma.

CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model.

Background/objectives: CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding.

Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells.

We have used a computational approach to identify anti-fibrotic therapies by querying a transcriptome. A transcriptome signature of activated hepatic stellate cells (HSCs), the primary collagen-secreting cell in liver, and queried against a transcriptomic database that quantifies changes in gene expression in response to 1,309 FDA-approved drugs and bioactives (CMap). The flavonoid apigenin was among 9 top-ranked compounds predicted to have anti-fibrotic activity; indeed, apigenin dose-dependently reduced collagen I in the human HSC line, TWNT-4.

Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis.

Background & Aims: Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5) mice develop more severe alcoholic fatty liver than Cyp2a5 mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism.

Alcohol Upregulation of CYP2A5: Role of Reactive Oxygen Species.

Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation.

Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity.

Autophagy is an intracellular pathway by which lysosomes degrade and recycle long-lived proteins and cellular organelles. The effects of ethanol on autophagy are complex but recent studies have shown that autophagy serves a protective function against ethanol-induced liver injury. Autophagy was found to also be protective against CYP2E1-dependent toxicity in vitro in HepG2 cells which express CYP2E1 and in vivo in an acute alcohol/CYPE1-dependent liver injury model.

Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro.

Clinical studies propose a causative link between the consumption of alcohol and the development and progression of liver disease in obese individuals. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects are additive or synergistic. In this study, we developed an in vitro model to address this question.

The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.

Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison.

Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice.

Background: Ethanol can induce cytochrome P450 2E1, an active generator of reactive oxygen species, and this cytochrome is considered a risk factor for oxidative liver injury. Recently, we found that in addition to P450 2E1 also cytochrome P450 2A5, another isoform of cytochrome P450, can be induced by ethanol, and that ethanol induction of cytochrome P450 2A5 is P450 2E1-dependent.

Aims: To investigate the role of cytochrome P450 2A5 in alcohol-induced liver injury.

Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications.

The cytochrome P450 mixed function oxidase enzymes play a major role in the metabolism of important endogenous substrates as well as in the biotransformation of xenobiotics. The liver P450 system is the most active in metabolism of exogenous substrates. This review briefly describes the liver P450 (CYP) mixed function oxidase system with respect to its enzymatic components and functions.

Methodology to assay CYP2E1 mixed function oxidase catalytic activity and its induction.

The cytochrome P450 mixed function oxidase enzymes are the major catalysts involved in drug metabolism. There are many forms of P450. CYP2E1 metabolizes many toxicologically important compounds including ethanol and is active in generating reactive oxygen species.

Synergistic toxic interactions between CYP2E1, LPS/TNFα, and JNK/p38 MAP kinase and their implications in alcohol-induced liver injury.

The mechanisms by which alcohol causes cell injury are not clear. 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 TNFα and to alcohol induction of CYP2E1.

HBx inhibits CYP2E1 gene expression via downregulating HNF4α in human hepatoma cells.

CYP2E1, one of the cytochrome P450 mixed-function oxidases located predominantly in liver, plays a key role in metabolism of xenobiotics including ethanol and procarcinogens. Recently, down-expression of CYP2E1 was found in hepatocellular carcinoma (HCC) with the majority to be chronic hepatitis B virus (HBV) carriers. In this study, we tested a hypothesis that HBx may inhibit CYP2E1 gene expression via hepatocyte nuclear factor 4α (HNF4α).

Multifactorial comparative proteomic study of cytochrome P450 2E1 function in chronic alcohol administration.

With the use of iTRAQ technique, a multifactorial comparative proteomic study can be performed. In this study, to obtain an overview of ethanol, CYP2E1 and gender effects on liver injury and gain more insight into the underlying molecular mechanism, mouse liver proteomes were quantitatively analyzed using iTRAQ under eight conditions including mice of different genders, wild type versus CYP2E1 knockout, and normal versus alcohol diet. A series of statistical and bioinformatic analyses were explored to simplify and clarify multifactorial comparative proteomic data.

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy.

Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis.

Inhibition of autophagy promotes CYP2E1-dependent toxicity in HepG2 cells via elevated oxidative stress, mitochondria dysfunction and activation of p38 and JNK MAPK.

Autophagy has been shown to be protective against drug and alcohol-induced liver injury. CYP2E1 plays a role in the toxicity of ethanol, carcinogens and certain drugs. Inhibition of autophagy increased ethanol-toxicity and accumulation of fat in wild type and CYP2E1 knockin mice but not in CYP2E1 knockout mice as well as in HepG2 cells expressing CYP2E1 (E47 cells) but not HepG2 cells lacking CYP2E1 (C34 cells).

Nicotine enhances ethanol-induced fat accumulation and collagen deposition but not inflammation in mouse liver.

Introduction: Alcohol and tobacco are frequently co-abused. Tobacco smoke increases alcoholic steatosis in apoE(-/-) mice. Tobacco smoke contains more than 4000 chemicals, but it is unknown which compounds in tobacco smoke play a major role in increasing alcoholic steatosis.

Cytochrome P450 2E1 potentiates ethanol induction of hypoxia and HIF-1α in vivo.

Ethanol induces hypoxia and elevates HIF-1α in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver, and liver injury. This study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1α in vivo and whether HIF-1α protects against or promotes CYP2E1-dependent toxicity in vitro.

Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability.

We have shown that alcohol increases Caco-2 intestinal epithelial cell monolayer permeability in vitro by inducing the expression of redox-sensitive circadian clock proteins CLOCK and PER2 and that these proteins are necessary for alcohol-induced hyperpermeability. We hypothesized that alcohol metabolism by intestinal Cytochrome P450 isoform 2E1 (CYP2E1) could alter circadian gene expression (Clock and Per2), resulting in alcohol-induced hyperpermeability. In vitro Caco-2 intestinal epithelial cells were exposed to alcohol, and CYP2E1 protein, activity, and mRNA were measured.

Nrf2 and antioxidant defense against CYP2E1 toxicity.

The transcription factor Nrf2 regulates the expression of important cytoprotective enzymes. Induction of cytochrome P450 2E1(CYP2E1) is one of the central pathways by which ethanol generates oxidative stress. CYP2E1 can be induced by ethanol and several low molecular weight chemicals such as pyrazole.