Abstract
Rosuvastatin calcium (ROV) and pravastatin sodium (PRA) are commonly used drugs for the treatment and prevention of cardiovascular diseases, but as a result, they have been reported to be present worldwide in aquatic environments. However, little is known about the effects of ROV or PRA on fish antioxidant systems and the underlying molecular mechanisms. In this study, zebrafish were exposed to ROV or PRA for 48 h, to explore their effects on the antioxidant response system in zebrafish liver and its possible molecular mechanism. The results showed that the contents of reactive oxygen species (ROS)and glutathione (GSH) increased significantly after ROV exposure, while the activities of catalase (CAT)and superoxide dismutase (SOD) were significantly inhibited. Glutathione peroxidase (GPx) and glutathione peroxidase (GST) were activated after exposure to 5 mg/L ROV, and malondialdehyde (MDA) content increased after 0.5 mg/L ROV exposure. Phosphoinositide 3-kinase (PI3K) and CAT were activated at the mRNA level only after 5 mg/L ROV exposure, while nuclear factor erythroid 2-like 2 (Nrf2) and SOD were inhibited at the protein level. After adding PI3K activator 740Y-P, the protein inhibition of Nrf2 and SOD was reversed. After PRA exposure, the contents of ROS, GSH and MDA were activated, the activities of CAT and SOD were significantly inhibited, and GST was activated only after 10 mg/L PRA exposure. At the mRNA level, 10mg/L PRA activated PI3K, CAT and GPx, while Nrf2 and SOD were inhibited at the protein level. Similarly, after the addition of the PI3K activator 740Y-P, inhibition of both Nrf2 and SOD protein was abolished. Further molecular docking simulations showed that ROV and PRA could spontaneously dock with PI3K and form stable interactions through hydrogen bonds. In summary, both ROV and PRA induce significant oxidative stress in zebrafish liver, and both ROV and PRA act as PI3K inhibitors to block the activation of the nuclear factor erythroid 2-like 2/antioxidant response element (Nrf2/ARE) signaling pathway, thereby reducing the antioxidant capacity in zebrafish liver.