Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: An explanation for high acetaminophen dosage in humans without hepatic injury

In studies designed to simulate a clinical observation in which an individu al became tolerant to normally lethal doses of acetaminophen (APAP), mice w ere pretreated with increasing doses of APAP for 8 days and challenged on d ay 9 with normally supralethal doses of APAP. These animals developed minim al hepatotoxicity after a challenge dose with a fourfold increase in LD50 t o 1,350 mg/kg, The pretreatment regimen resulted in hepatic changes includi ng: centrilobular localization of 3-(cysteine-S-yl)APAP protein adducts, se lective down-regulation of cytochrome P4502E1 (CYP2E1) and CYP1A2 that prod uced the toxic metabolite, N-acetyl-p-benzoquinone imine, higher levels of reduced glutathione (GSH), centrilobular inflammation, and a fourfold incre ase in hepatocellular proliferation. The protection against the lethal APAP doses afforded by pretreatment is secondary to these changes and to the as sociated regional shift in the bioactivation of the APAP challenge dose fro m centrilobular to periportal regions where CYP2E1 is not found, protective GSH is more abundant, and where cell-proliferative responses are better ab le to sustain repair. This shift in APAP bioactivation results in less-inte nse covalent binding that is more diffuse and spread uniformly throughout t he hepatic lobe, most likely contributing to protection by delaying the ear ly onset of liver injury that has been generally associated with centrilobu lar localization of the adducts, Intervention of APAP pretreatment-induced cell division in mice with colchicine left them resistant to a 500-mg/kg (n ormally lethal) dose of APAP, but unable to survive a 1,000-mg/kg APAP chal lenge dose. The data demonstrate multiple mechanistic components to the pro tection afforded by APAP pretreatment, Whereas metabolic and physiological changes not dependent on cell proliferation are adequate to protect against 500 mg/kg APAP, these changes plus a potentiated cell-proliferative respon se are necessary for protection against the supralethal 1,000-mg/kg APAP do se. Furthermore, the data document an uncoupling of the traditional associa tion between covalent binding and toxicity, and suggest that the assessment of toxicity following repeated or chronic APAP exposure must consider alte red drug interactions and parameters besides those historically used to ass ess acute overdose.