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.