CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload

Abstract

CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.

In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia

“…Recent studies suggest that CYP2E1 plays an indispensable role in the development and progression of NAFLD [ 33 ], adapting its role during different phases. CYP2E1 maintains hepatic lipid homeostasis and, according to some animal studies, complements CYP4A enzymes during lipid utilization and oxidative stress, in particular, lipoperoxidation [ 34 ]. In the present study, increased mRNA expression in Cyp2e1, along with decreased expression of Cyp4a1 and Cyp4a2, improved lipid accumulation following empagliflozin treatment.…”

Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver

“…In this section, we review important features of CYP2E1 but readers who want to get further information on this enzyme are invited to peruse several excellent reviews [ 1 , 2 , 6 , 7 , 8 , 9 ]. Beforehand, it should be underscored that a significant part of the knowledge gathered so far on CYP2E1 was actually inferred from studies that did not discriminate between CYP2E1 located in the endoplasmic reticulum (ER, also referred to as microsomal CYP2E1) and mtCYP2E1.…”

“…Among the different CYPs expressed in humans, hepatic cytochrome P450 2E1 (CYP2E1, formerly referred to as P450j) has a unique place in liver pathophysiology. Indeed, CYP2E1 is central to the occurrence of different acute and chronic liver diseases induced by drugs, toxicants and alcohol abuse [ 1 , 2 ]. Moreover, there is increasing evidence that CYP2E1 plays a significant role in obesity-associated nonalcoholic fatty liver disease (NAFLD), in particular by favoring the progression of simple fatty liver (i.e., steatosis) to nonalcoholic steatohepatitis (NASH) [ 2 , 3 ].…”

“…Indeed, CYP2E1 is central to the occurrence of different acute and chronic liver diseases induced by drugs, toxicants and alcohol abuse [ 1 , 2 ]. Moreover, there is increasing evidence that CYP2E1 plays a significant role in obesity-associated nonalcoholic fatty liver disease (NAFLD), in particular by favoring the progression of simple fatty liver (i.e., steatosis) to nonalcoholic steatohepatitis (NASH) [ 2 , 3 ]. Although the historically more studied localization of CYP2E1 is the endoplasmic reticulum (ER), this enzyme is also found in significant amounts in mitochondria [ 4 , 5 ].…”

Drug Repurposing in Alternative Medicine: Sochehwan, a Polyherbal Traditional Korean Digestant, Protects against Alcoholic Steatohepatitis by Regulating Cytochrome P450 2E1 Expression

“…As a member of the classical cytochrome P450 family (CYP 450), CYP2E1 is regarded as a major source of alcohol-or drug-induced reactive oxygen species (ROS) in the liver [5]. CYP2E1 is directly involved in alcohol metabolism and converts ethanol into acetaldehyde [6].…”