Acetaminophen is a mild analgesic and antipyretic agent known to cause centrilobular hepatic necrosis at toxic doses. Although this may be due to a direct interaction of reactive acetaminophen metabolites with hepatocyte proteins, recent studies have suggested that cytotoxic mediators produced by parenchymal and nonparenchymal cells also contribute to the pathophysiological process. Nitric oxide is a highly reactive oxidant produced in the liver in response to inflammatory mediators. In the present studies we evaluated the role of nitric oxide in the pathophysiology of acetaminophen-induced liver injury. Treatment of male Long Evans Hooded rats with acetaminophen (1 g/kg) resulted in damage to centrilobular regions of the liver and increases in serum transaminase levels, which were evident within 6 hours of treatment of the animals and reached a maximum at 24 hours. This was correlated with expression of inducible nitric oxide synthase (iNOS) protein in these regions. Hepatocytes isolated from both control and acetaminophen-treated rats were found to readily synthesize nitric oxide in response to inflammatory stimuli. Cells isolated from acetaminophen-treated rats produced more nitric oxide than cells from control animals. Production of nitric oxide by cells from both control and acetaminophen-treated rats was blocked by aminoguanidine, a relatively specific inhibitor of iNOS. Arginine uptake and metabolism studies revealed that the inhibitory effects of aminoguanidine were due predominantly to inhibition of iNOS enzyme activity. Pretreatment of rats with aminoguanidine was found to prevent acetaminophen-induced hepatic necrosis and increases in serum transaminase levels. This was associated with reduced nitric oxide production by hepatocytes. Inhibition of toxicity was not due to alterations in acetaminophen metabolism since aminoguanidine had no effect on hepatocyte cytochrome P4502E1 protein expression or N-acetyl-pbenzoquinone-imine formation. Taken together, these data demonstrate that nitric oxide is an important mediator of acetaminophen-induced hepatotoxicity. (HEPATOLOGY 1998; 26:748-754.)

DNA condensation plays a vital role in regulating cell life. Herein, we report a supramolecular complex with synergistic and specific DNA‐condensing ability, which is achieved by the cucurbituril‐induced conformational change and pKa shift in aqueous solution. The complexation with cucurbit[6]uril can drive the side chain of 1,6‐diaminohexane out of β‐cyclodextrin's cavity to increase the molecular rigidity and meanwhile, the supramolecular pKa shift from 10.81 to 12.15 can ensure the amount of positive charges, which facilitate the close contact with DNA. By benefiting from β‐cyclodextrin's hydrophobic cavity, the binary cucurbituril–cyclodextrin complex can be further decorated with anthryl adamantane. Furthermore, it is demonstrated that the resultant ternary assembly originating from the integration of cucurbituril–cyclodextrin macrocyclic pair with the protonated ammonium chain and π‐conjugated anthryl adamantane can efficiently bind to the DNA backbones, thus resulting in the DNA morphological transition from loose clews to compact nanoparticles. Thus, this supramolecular complex may have powerful potential as compacting agent for nucleic acids in non‐viral gene delivery.