Abstract
Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis. Indeed, increased CYP2E1 activity in nonalcoholic fatty liver disease (NAFLD) is deemed to induce reactive oxygen species overproduction, which in turn triggers oxidative stress, necroinflammation and fibrosis. In 1997, Avadhani’s group reported for the first time the presence of CYP2E1 in rat liver mitochondria, and subsequent investigations by other groups confirmed that mitochondrial CYP2E1 (mtCYP2E1) could be found in different experimental models. In this review, we first recall the main features of CYP2E1 including its role in the biotransformation of endogenous and exogenous molecules, the regulation of its expression and activity and its involvement in different liver diseases. Then, we present the current knowledge on the physiological role of mtCYP2E1, its contribution to xenobiotic biotransformation as well as the mechanism and regulation of CYP2E1 targeting to mitochondria. Finally, we discuss experimental investigations suggesting that mtCYP2E1 could have a role in alcohol-associated liver disease, xenobiotic-induced hepatotoxicity and NAFLD.
Highlights
Cytochromes P450 (CYPs) are phase I enzymes involved in the metabolism of numerous endogenous and exogenous compounds
Physiological expression of hepatic Cytochrome P450 2E1 (CYP2E1) is mainly regulated by the transcription factors hepatocyte nuclear factor 1-α (HNF–1α) [19,20] and β-catenin [21], recent investigations uncovered a significant role of Krüppel-Like Factor 15 (KLF15) [22]
This toxicity is mostly secondary to the formation of reactive metabolites, CYP2E1 induction could play a role by itself via reactive oxygen species (ROS) production from molecular oxygen
Summary
Cytochromes P450 (CYPs) are phase I enzymes involved in the metabolism of numerous endogenous and exogenous compounds. These enzymes are mainly expressed in the liver but are present in other tissues including gut, kidney, lung, nasal mucosa, peripheral blood mononuclear cells (PBMCs), male and female reproductive tissues, adrenal glands and brain. The historically more studied localization of CYP2E1 is the endoplasmic reticulum (ER), this enzyme is found in significant amounts in mitochondria [4,5]. This location is not trivial because mitochondria are the powerhouses of the cells and as such, CYP2E1-induced impairment of mitochondrial function can have dire consequences on cell homeostasis. We discuss in depth the current available data on mitochondrial CYP2E1 (mtCYP2E1), in particular regarding xenobiotic biotransformation and its emerging role in different liver diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
