Adverse Outcome Pathway on Cyp2E1 activation leading to liver cancer
The present AOP describes the prolonged activation of Cyp2E1 resulting in liver cancer.
Cyp2E1 is a cytochrome P450 mono-oxygenase that bioactivates over 85 substrates, thereby
creating electrophilic metabolites and oxidative stress. Mono-oxygenation of these
substrates to their reactive metabolites, and the accompanying oxidative stress produced
during metabolism, pose health risks because they lead to hepatotoxicity and, often,
to liver cancer.
The MIE occurs when Cyp2E1 binds a substrate. The Cyp2E1 catalytic cycle is prone
to decoupling, which produces oxidative stress (KE1), and mono-oxidation of substrates
produces reactive metabolites. Both reactive oxygen species and metabolites cause
cytotoxicity (KE2). However, following injury, the liver is able to regenerate itself
through an increase in cellular proliferation (KE3). Under conditions of chronic activation
of Cyp2E1, excessive chronic increases in levels of reactive oxygen species and cell
death, and subsequent dysregulated cellular proliferation, leads to tumour formation
Published on October 15, 2021
In series:OECD Series on Adverse Outcome Pathwaysview more titles