NOVEL THERAPIES FOR ACETAMINOPHEN TOXICITY
Principal Investigator: L P James
Abstract: DESCRIPTION (adapted from the application) 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.
Funding Period: 2001-02-15 - 2005-11-30
more information: NIH RePORT
- Tumour necrosis factor receptor 1 and hepatocyte regeneration in acetaminophen toxicity: a kinetic study of proliferating cell nuclear antigen and cytokine expressionLaura P James
Department of Paediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
Basic Clin Pharmacol Toxicol 97:8-14. 2005..Depletion of tumour necrosis factor receptor 1 has long-lasting effects on hepatocyte regeneration in acetaminophen toxicity but multiple other factors appear to orchestrate eventual recovery in these mice...
- Cytokines and toxicity in acetaminophen overdoseLaura P James
Department of Pediatrics, Section of Clinical Pharmacology and Toxicology, Arkansas Children s Hospital, 800 Marshall Street, Little Rock, AR 72202, USA
J Clin Pharmacol 45:1165-71. 2005..An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity...
- Induction of the nuclear factor HIF-1alpha in acetaminophen toxicity: evidence for oxidative stressLaura P James
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Biochem Biophys Res Commun 343:171-6. 2006..Thus, HIF-1alpha is induced before APAP toxicity and can occur under non-hypoxic conditions. The data suggest a role for oxidative stress in the induction of HIF-1alpha in APAP toxicity...
- Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicityBrian Donahower
Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Am J Physiol Gastrointest Liver Physiol 291:G102-9. 2006..These data indicate that endogenous VEGF is critically important to the process of hepatocyte regeneration in APAP-induced hepatotoxicity in the mouse...