Biol. Pharm. Bull. 29(8) 1618—1624 (2006)

in various in vivo and in vitro experiments. The use of this solvent is favored especially when physicochemical properties of a test compound have not been well characterized such as in the case of natural products. But DMSO is not biologically inert. DMSO has numerous pharmacological effects, the most well-known of which is hydroxyl radical scavenging capacity. Therefore, it is suspected that toxicological implications of the interaction of DMSO with a xenobiotic, either directly or indirectly via body system, would be complex. Acetaminophen (APAP), a widely used analgesic-antipyretic, is detoxified rapidly through formation of sulfate and glucuronide conjugates. However, at large doses this drug is increasingly converted into a reactive metabolite, Nacetyl-p-benzoquinonimine (NAPQI). The metabolic activation of APAP in human is mediated by CYP2E1, 1A2 and 3A4. The relative contribution of each CYP isozyme to formation of the toxic metabolite is not clear, however, it has been generally accepted that CYP2E1 has the principal role in metabolic activation of this drug both in human and rodents. The reactive metabolite is normally detoxified by conjugation with glutathione (GSH), subsequently resulting in generation of APAP-mercapturate via APAP-cysteine. When generation of the reactive metabolite exceeds the availability of GSH for conjugation reaction, covalent binding of the metabolite to macromolecules may result, an event that correlates with induction of hepatic necrosis. Therefore, the most important determinants for induction of APAP toxicity are the metabolic activities catalyzing its activation and the effectiveness of GSH conjugation reaction. It has been shown that induction of APAP hepatotoxicity may be decreased by a dose of DMSO in mice and also in hamsters. In mice DMSO was found to decrease covalent binding of APAP metabolites to hepatic protein, but the microsomal aniline hydroxylase activity was rather increased. Accordingly, the authors suggested that the protective effect of DMSO was due to interaction of DMSO with free radicals or reactive APAP metabolites. Later studies revealed that the protection provided by DMSO was tissue-specific, which would exclude the possibility of involvement of a nonspecific mechanism such as scavenging of free radicals. Also DMSO was shown to inhibit the biliary concentration of APAP-GSH and the microsomal dimethylnitrosamine Ndemethylase activity. Therefore, it appears that the protective effect of DMSO against APAP liver toxicity is associated with inhibition of CYP-dependent activation of this drug. Meanwhile, conflicting results were demonstrated in studies examining the effects of DMSO on metabolism and toxicity of other xenobiotics that are also metabolically activated by CYP2E1. For instance, DMSO was shown to enhance the hepatotoxicity of carbon tetrachloride (CCl4), 10) while other studies demonstrated reduction of CCl4-induced hepatotoxicity in rats and mice. Different studies showed that the hepatotoxicity of CCl4 or its congener, chloroform (CHCl3), was not altered by DMSO. More recently Lind and colleagues demonstrated that CHCl3 hepatotoxicity was decreased by DMSO given as late as 24 h after CHCl3, and suggested that the protective effect of DMSO could not be explained by a decrease in metabolic conversion of this substance to a reactive metabolite. The inconsistency in the effects of DMSO on metabolism and toxicity of xenobiotics suggests that this solvent may induce multiple actions on the metabolic reaction mediated by CYP2E1. In this study we examined the changes in generation of metabolic products from APAP and the resulting he1618 Vol. 29, No. 8