Acetaminophen increases the risk of arsenic-mediated development of hepatic damage in rats by enhancing redox-signaling mechanism.

We evaluated whether the commonly used analgesic-antipyretic drug acetaminophen can modify the arsenic-induced hepatic oxidative stress and also whether withdrawal of acetaminophen administration during the course of long-term arsenic exposure can increase susceptibility of liver to arsenic toxicity. Acetaminophen was co-administered orally to rats for 3 days following 28 days of arsenic pre-exposure (Phase-I) and thereafter, acetaminophen was withdrawn, but arsenic exposure was continued for another 28 days (Phase-II). Arsenic increased lipid peroxidation and reactive oxygen species (ROS) generation, depleted glutathione (GSH), and decreased superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR) activities. Acetaminophen caused exacerbation of arsenic-mediated lipid peroxidation and ROS generation and further enhancement of serum alanine aminotransferase and aspartate aminotransferase activities. In Phase-I, acetaminophen caused further GSH depletion and reduction in SOD, catalase, GPx and GR activities, but in Phase-II, only GPx and GR activities were more affected. Arsenic did not alter basal and inducible nitric oxide synthase (iNOS)-mediated NO production, but decreased constitutive NOS (cNOS)-mediated NO release. Arsenic reduced expression of endothelial NOS (eNOS) and iNOS genes. Acetaminophen up-regulated eNOS and iNOS expression and NO production in Phase-I, but reversed these effects in Phase-II. Results reveal that acetaminophen increased the risk of arsenic-mediated hepatic oxidative damage. Withdrawal of acetaminophen administration also increased susceptibility of liver to hepatotoxicity. Both ROS and NO appeared to mediate lipid peroxidation in Phase-I, whereas only ROS appeared responsible for peroxidative damage in Phase-II.