Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

Abstract

Dimethylsulfoxide (DMSO) is frequently used as a solvent 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. 1) 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 3A4.2,3) 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.4) 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 5) and also in hamsters. 6) In mice DMSO was found to decrease covalent binding of APAP metabolites to hepatic protein, but the microsomal aniline hydroxylase activity was rather increased. 7)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. 8) Also DMSO was shown to inhibit the biliary concentration of APAP-GSH and the microsomal dimethylnitrosamine Ndemethylase activity. 9) 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 (CCl 4 ), 10) while other studies demonstrated reduction of CCl 4 -induced hepatotoxicity in rats and mice. 11,12) Differ...

Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity

“…DMSO has been commonly used in biological studies as an inert solvent to dissolve drugs with low water solubility. However, DMSO has been known to attenuate liver injury induced by APAP overdose in rodents, and often the facts confound evaluation of the protective effects of compounds with poor water solubility against APAP-induced liver injury (47,48). In this study, we also confirmed that the treatment with 5% DMSO attenuated the increase in serum alanine aminotransferase levels and hepatocellular necrosis induced by APAP (400 mg/kg, i.p.)…”

Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity

“…A study reported protection against APAP hepatotoxicity with a pan-caspase inhibitor in the absence of caspase activation (El-Hassan et al, 2003). However, the protection was caused by the solvent (dimethyl sulfoxide, DMSO) (Jaeschke et al, 2006), which is an effective inhibitor of P450 enzymes (Yoon et al, 2006). On the other hand, in cases of Fas- or TNF-induced hepatocellular apoptosis, caspase inhibitors are highly effective and completely eliminate cell death (Bajt et al, 2000; Jaeschke et al, 1998).…”

Experimental models of hepatotoxicity related to acute liver failure

“…One of the most effective ways to prevent APAP toxicity is to interfere with the initial step of metabolic activation. Many solvents, such as dimethyl sulfoxide or ethanol, used to dissolve agents with limited water solubility effectively, compete with APAP for CYP metabolism even at very low doses (Jaeschke et al 2006; Park et al 1988; Sato and Lieber 1981; Yoon et al 2006). Extracts from plants and other sources contain numerous chemicals that can act as CYP inhibitors (Jiang et al 2015), but are rarely tested for this effect.…”