Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

Abstract

Effects of dimethylsulfoxide (DMSO) on metabolism and toxicity of acetaminophen (APAP) were examined using male mice. A dose of DMSO (1 ml/kg, i.p.) inhibited the induction of APAP hepatotoxicity almost completely as indicated by changes in serum hepatotoxic parameters. Quantification of major APAP metabolites in plasma showed that APAP-glutathione (GSH), a conjugate generated via metabolic activation of APAP, was reduced significantly while APAP-sulfate and APAP-glucuronide, detoxified metabolites both produced directly from the parent drug, were increased in mice pretreated with DMSO. However, microsomal CYP2E1 activity measured with p-nitrophenol and p-nitroanisole as substrates was increased by DMSO treatment. Generation of APAP-GSH in microsomes from control mice was inhibited by DMSO in a dose-dependent manner. Lineweaver-Burk plot analysis indicated that the inhibition pattern produced by DMSO was competitive in nature. A 10000 g supernatant was reconstituted with the cytosolic fraction and microsomes from DMSO- or saline-treated animals. APAP-GSH production was increased significantly when the cytosolic fraction from saline-treated mice and/or microsomes from DMSO-treated mice were used. The results indicate that DMSO induces the enzyme activity responsible for oxidative metabolism of APAP, but its direct inhibitory effect on the enzymatic interaction with this drug decreases the overall production of a reactive metabolite, resulting in reduction of the hepatotoxicity. It is suggested that DMSO effects on metabolism of a xenobiotic would vary depending on its potential to inhibit the interaction of enzyme(s) and the xenobiotic.