Abstract

Acetaminophen (APAP) is a widely used, safe, antipyretic analgesic which, when taken in excess doses, causes seveere hepatic necrosis. Hepatoxicity has been shown to be the result of microsomal activation of APAP to an electrophile which first depletes glutathione (GSH) reserves and then binds covalently to critical cell components. The proposed research is aimed at elucidating the mechnism(s) hwereby APAP causes cell death. The following specific questions will be addressed: 1) How is covalent binding to different subcellular organelles related to the development of the hepatotoxicity? 2) How is APAP alteration of organelle structure and function related to the hepatotoxocity? 3) Can the toxic process leading to APAP toxicity be modulated after covalent binding has occurred? 4) Does GSH have an additional protective role against APAP hepatotoxicity after miximal covalent binding has occurred? 5) What is the role of lipid peroxidation in subcellular organelles in the development of APAP-induced hepatotoxicity? The approach will involve determining the sequence of biochemical and morphological alterations which occur in hepatocytes subsequent to exposure to a hepatotoxic concentration of APAP. Specifically, we will study the dose and time response profile of APAP electrophile covalent binding to specific organelles and compare this with APAP effects upon organelle structure and function as well as correlate such effects to the acute hepatotoxic effects of APAP. Special attention will be given to elucidation of the effects of APAP on plasma membrane structure and function. In addition, lipid peroxidation will be measured in specific organelles and, glutathione depletion or enhancement will be employed in attempts to modulate toxicity while monitoring selected parameters from the dose and time studies. The proposed research will elucidate the events which occur during APAP poisoning and will permit the development of rational alternative therapies for the prevention of severe hepatotoxicity after exposure to normally hepatoxic doses of APAP and other hepatotoxins.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031460-03
Application #
3279461
Study Section
Toxicology Study Section (TOX)
Project Start
1984-08-01
Project End
1988-03-31
Budget Start
1986-08-01
Budget End
1988-03-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Connecticut
Department
Type
Schools of Pharmacy
DUNS #
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269

  Publications

Slitt, Angela M Lucas; Dominick, Pamela K; Roberts, Jeanette C et al. (2005) Effect of ribose cysteine pretreatment on hepatic and renal acetaminophen metabolite formation and glutathione depletion. Basic Clin Pharmacol Toxicol 96:487-94
Slitt, Angela Lucas; Dominick, Pamela K; Roberts, Jeanette C et al. (2004) Standard of care may not protect against acetaminophen-induced nephrotoxicity. Basic Clin Pharmacol Toxicol 95:247-8
Lucas, A M; Hennig, G; Dominick, P K et al. (2000) Ribose cysteine protects against acetaminophen-induced hepatic and renal toxicity. Toxicol Pathol 28:697-704
Boulares, A H; Giardina, C; Inan, M S et al. (2000) Acetaminophen inhibits NF-kappaB activation by interfering with the oxidant signal in murine Hepa 1-6 cells. Toxicol Sci 55:370-5
Boulares, H A; Giardina, C; Navarro, C L et al. (1999) Modulation of serum growth factor signal transduction in Hepa 1-6 cells by acetaminophen: an inhibition of c-myc expression, NF-kappaB activation, and Raf-1 kinase activity. Toxicol Sci 48:264-74
Boess, F; Bopst, M; Althaus, R et al. (1998) Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-alpha gene knockout mice. Hepatology 27:1021-9
Cohen, S D; Khairallah, E A (1997) Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab Rev 29:59-77
Cohen, S D; Pumford, N R; Khairallah, E A et al. (1997) Selective protein covalent binding and target organ toxicity. Toxicol Appl Pharmacol 143:1-12
Navarro, C L; Cohen, S D; Khairallah, E A (1996) Genes encoding the acetaminophen and selenium binding proteins map to mouse chromosome 3. Mamm Genome 7:919-20
Emeigh Hart, S G; Wyand, D S; Khairallah, E A et al. (1996) Acetaminophen nephrotoxicity in the CD-1 mouse. II. Protection by probenecid and AT-125 without diminution of renal covalent binding. Toxicol Appl Pharmacol 136:161-9

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