Cytochrome P450-dependent reactive oxygen species (ROS) production contributes to Mn3O4 nanoparticle-caused liver injury

Abstract

Mn₃O₄ 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 Mn₃O₄ NPs using a long-term exposure model. After exposure to the Mn₃O₄ NPs for 60–120 days, rats preferentially accumulated manganese in the livers. Histopathological observation and apoptosis assays revealed that the Mn₃O₄ 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 Mn₃O₄ NP-caused liver injury, but had no impact on the expression of CYP1A2. These results indicated that the toxicity of the Mn₃O₄ 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.