Acetaminophen (APAP) is the major cause of acute liver failure (ALF) in the U.S. The antidote, N- acetylcysteine (NAC), increases hepatic GSH, decreases covalent binding and is highly effective in the early stages of toxicity. However, after the onset of toxicity, NAC has limited efficacy and there is a high incidence of liver transplant or death in these patients. This proposal will investigate mechanisms of repair of APAP-induced toxicity because novel therapies are possible with augmentation of innate repair mechanisms in ALF secondary to APAP. Our preliminary studies reveal mechanisms of hepatocyte regeneration that are critical to recovery in the late stages of APAP mediated ALF. Oxidative stress, hypoxia inducible factor 1 alpha (HIF-1?) and vascular endothelial growth factor (VEGF) appear to play central roles in the liver's response to APAP toxicity. We show that HIF-1? and VEGF are dramatically increased in the livers of APAP intoxicated mice. Also, treatment with a VEGF inhibitor markedly delays hepatocyte regeneration. It is well established, in other model systems, that HIF-1? can regulate the levels of VEGF, however this has not been previously investigated in the liver. VEGF is an angiogenic factor important in organ repair. Although hypoxia is a well described mechanism of HIF-1? induction in many models, our recent data indicate that oxidative stress induces HIF-1? and is central to APAP mediated ALF. We have shown that HIF-1? is induced in freshly isolated mouse hepatocytes treated with APAP under normoxic conditions and blocked by inhibitors of oxidative stress. Using freshly isolated hepatocytes, we recently reported that APAP induced oxidative stress and mitochondrial permeability transition leading to cellular necrosis. We will test the three following hypotheses: 1) Oxidative stress leads to HIF-1? induction in APAP-mediated hepatotoxicity in mice. 2) Nuclear factor HIF-1? is critical for upregulation of VEGF synthesis in APAP toxicity in mice. 3) The interactions of VEGF and its receptors are critical to hepatocyte regeneration following APAP toxicity in mice. Lay description: This project will examine mechanisms of repair in the liver following acetaminophen toxicity in mice treated with acetaminophen. A better understanding of the recovery processes of the liver will lead to the development of new treatments for acute liver failure. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK075936-01A1
Application #
7255976
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Serrano, Jose
Project Start
2007-08-24
Project End
2012-05-31
Budget Start
2007-08-24
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$252,000
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pediatrics
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Bhattacharyya, Sudeepa; Yan, Ke; Pence, Lisa et al. (2014) Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children. Biomark Med 8:147-59
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Cohen-Wolkowiez, Michael; Ouellet, Daniele; Smith, P Brian et al. (2012) Population pharmacokinetics of metronidazole evaluated using scavenged samples from preterm infants. Antimicrob Agents Chemother 56:1828-37
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Cohen-Wolkowiez, Michael; Benjamin Jr, Daniel K; Ross, Ashley et al. (2012) Population pharmacokinetics of piperacillin using scavenged samples from preterm infants. Ther Drug Monit 34:312-9

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