Cytochrome P450-dependent reactive oxygen species (ROS) production contributes to Mn(3)O(4) nanoparticle-caused liver injury

Mn(3)O(4) nanoparticles (NPs) are one of the most important nanomaterials, and have a wide range of applications (i.e., catalysis, solar-electron transformation and molecular adsorption). However, their biological effect remains to be detailed. In this study, we investigated the in vivo toxicity of the synthesized Mn(3)O(4) NPs using a long-term exposure model. After exposure to the Mn(3)O(4) NPs for 60–120 days, rats preferentially accumulated manganese in the livers. Histopathological observation and apoptosis assays revealed that the Mn(3)O(4) NPs caused severe liver injury associated with apoptosis. Transcription profiling analysis, immune histochemistry (IHC) staining and western blotting showed that the NPs significantly up-regulated expression of the cytochrome P450 (CYP1A2). Accordingly, the NP-treated livers exhibited high levels of reactive oxygen species (ROS) and oxidative damage. Moreover, ROS scavenging by N-acetylcysteine (NAC) attenuated Mn(3)O(4) NP-caused liver injury, but had no impact on the expression of CYP1A2. These results indicated that the toxicity of the Mn(3)O(4) NPs was attributed to cytochrome P450-dependent ROS accumulation and consequent oxidative damage. This study uncovers the contribution of cytochrome P450-induced oxidative stress to nanotoxicity.