The Cytoprotective Role of Cytochrome P450 2A5 against Oxidative Stress in Mouse Liver

Cytochrome P450 2A5 (CYP2A5) is involved in the oxidative metabolism of several endogenous substrates and xenobiotics such as nicotine, coumarin and several pro-carcinogens. CYP2A5 is up-regulated and induced by structurally unrelated hepatotoxins, whereas levels of most other CYPs remain unchanged or are down-regulated. CYP2A5 induction is mediated by the Nrf-2 response pathway, a major mechanism facilitating cellular defence against oxidative stress and an increase in the detoxification of xenobiotics. We hypothesized that CYP2A5 has a cytoprotective role against hepatocellular oxidative stress by reducing levels of reactive oxygen species (ROS). This study assessed the influence of CYP2A5 on cell death and the level of oxidative stress in cultured mouse hepatocytes treated with various pro-oxidants. Further, we evaluated the effect of CYP2A5 levels on pyrazole-induced oxidative stress in mouse liver in vivo. Our results demonstrate that CYP2A5 plays a cytoprotective against oxidative stress by reducing ROS levels and apoptosis induced by pro-oxidants. Our study is the first to show a cytoprotective role of CYP2A5 against oxidative stress, which is a unique functional capability among CYP enzymes.