Protection by dimethylsulfoxide against acetaminophen-induced hepatic, but not respiratory toxicity in the mouse.
Dimethylsulfoxide (DMSO) is used as a vehicle for the administration of compounds that are difficult to solubilize. Acetaminophen (AP), typically administered ip in hot basic saline, dissolves readily in DMSO. However, since DMSO acts as a free radical scavenger in vitro, and since AP toxicity may be mediated through oxidative stress, we examined the possibility that DMSO might protect against AP toxicity. Survival of mice 96 hr after AP (900 mg/kg ip) was increased from 10 to 60% by concomitant DMSO administration (4 g/kg sc). Adult female Swiss inbred mice given AP (800 mg/kg ip in hot basic saline) exhibited severe centrilobular hepatic necrosis, pulmonary nonciliated bronchiolar epithelial (Clara cell) necrosis and nasal epithelial necrosis. DMSO (8 g/kg 50% in saline) protected against AP hepatotoxicity, whether administered prophylactically (14.5 and 2.5 hr before AP), concomitantly with AP, or antidotally (30 or 60 min post-AP). No treatment protected against pulmonary Clara cell damage. Nor did pretreatment with DMSO protect against AP-induced necrosis of nasal epithelium. Other treatment regimes were not evaluated for their effect on nasal epithelial toxicity. Since DMSO protection is tissue specific, it does not appear to be mediated by a nonspecific mechanism, such as scavenging of free radicals. Six hours after AP, glutathione (GSH) levels had dropped significantly in liver, but not in lung. AP-induced loss of hepatic GSH was slowed by DMSO even in the presence of BSO, an inhibitor of GSH synthesis. These findings are consistent with decreased utilization of GSH, due to decreased bioactivation of AP or decreased turnover of GSH.
Jeffery
E H
EH
Institute for Environmental Studies, College of Veterinary Medicine, University of Illinois, Urbana 61801.
Haschek
W M
WM
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D005260:Female; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008168:Lung / Q000187:drug effects; D051379:Mice; D009336:Necrosis; D012137:Respiratory System / Q000187:drug effects* / Q000473:pathology
D005609:Free Radicals; D000082:Acetaminophen; D002251:Carbon Tetrachloride; D005978:Glutathione; D004121:Dimethyl Sulfoxide