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The long term goal of this award is to develop therapies, based on new mechanistic data, that can be utilized in the treatment of the acetaminophen (APAP) overdose patient. At therapeutic doses, APAP is metabolized to the reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by glutathione (GSH). With overdose, GSH is depleted and NAPQI covalently binds to proteins. The antidote, N-acetylcysteine (NAC) increases hepatic GSH and detoxifies NAPQI but its efficacy beyond 16 hrs is controversial. Hepatotoxicity is usually not evident until 48-72 hrs. The mechanism of the late phase of toxicity is unknown. Recent work has shown that activation of inflammatory mediators occurs with toxicity. It has been demonstrated in a murine model that nitrotyrosine adducts, acetaminophen-protein adducts, and toxicity co-localize in the same centrilobular cells. Nitrotyrosine occurs via peroxynitrite, a species formed from nitric oxide (NO) and superoxide. NO synthesis correlates with toxicity; iNOS knockout mice are less susceptible to toxicity; and Kupffer cell/macrophage inactivators decrease toxicity and tyrosine nitration. We postulate that the late phase in human toxicity (16-72 hrs) is a result of activation of Kupffer cells/macrophages, and possibly other cells, leading to the formation of peroxynitrite and inflammatory mediators. We hypothesize that treatments that decrease peroxynitrite formation can be effectively utilized to treat patients in the late phase of toxicity. This hypothesis will be tested through the following Specific Aims: 1.) Evaluate the involvement of pro- and anti-inflammatory cytokines in APAP hepatotoxicity and the effect of cytokine modulation on hepatotoxicity in the mouse. 2.) Evaluate the efficacy of continuous infusion NAC in the late phase of toxicity. (Oral NAC has a very low bioavailability). 3.) Examine the time course of nitrotyrosine adducts and inflammatory cytokines in the APAP overdose patient. The development of this applicant into an independent researcher will be accomplished through this proposal performed under the guidance of well-established mentors, in a university research environment, with training in various analytical methods to assess drug toxicity in animal models.

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