Abstract

The hepatotoxicity of carbon tetrachloride (CCl4) is primarily a result of electrophilic metabolites such as the trichloromethyl radical (.CCl3). Yet, the mechanism(s) by which .CCl3 causes cell death are still unresolved. The primary objectives of these studies are to demonstrate that: 1) membrane (endoplasmic reticulum) phospholipids such as phosphatidylcholine (PC) are critical targets of .CCl3; 2) the cytosol is a reservoir of rapidly activated (translocation) enzymes that regulate the degradation (phospholipase C) and biosynthesis (phosphocholine cytidylyltransferase) of membrane (PC); 3) the formation of membrane PC.CCl3 adducts results in rapid, enzyme (cytosolic) mediated alterations in membrane PC metabolism and content that are critical events in .CCl3- dependent liver cell death. The validity of these concepts will be established by assessing the influence of CC14 and several CC14 structural analogues (CBrCl3, CHCl3, and CFCl3) on liver cell phospholipid degradation, biosynthesis and content in vivo and in vitro. Experimental conditions will be selected which increase (phenobarbital induction) and decrease (metrypone and SKF 525A) the formation of electrophilic metabolites and chemical- dependent hepatotoxicity. These studies will increase our understanding of how reactive chemical metabolites cause liver cell injury. This information is crucial to our understanding of how to prevent and treat chemical-dependent liver cell necrosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031115-08
Application #
3229882
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1983-02-01
Project End
1992-08-31
Budget Start
1990-09-01
Budget End
1992-08-31
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298

  Publications

Kim, Yoonkyung; Klutz, Athena M; Jacobson, Kenneth A (2008) Systematic investigation of polyamidoamine dendrimers surface-modified with poly(ethylene glycol) for drug delivery applications: synthesis, characterization, and evaluation of cytotoxicity. Bioconjug Chem 19:1660-72
Ivanov, Andrei A; Jacobson, Kenneth A (2008) Molecular modeling of a PAMAM-CGS21680 dendrimer bound to an A2A adenosine receptor homodimer. Bioorg Med Chem Lett 18:4312-5
Palaniappan, Krishnan K; Gao, Zhan-Guo; Ivanov, Andrei A et al. (2007) Probing the binding site of the A1 adenosine receptor reengineered for orthogonal recognition by tailored nucleosides. Biochemistry 46:7437-48
Jacobson, Kenneth A; Gao, Zhan-Guo; Liang, Bruce T (2007) Neoceptors: reengineering GPCRs to recognize tailored ligands. Trends Pharmacol Sci 28:111-6
Gao, Zhan-Guo; Duong, Heng T; Sonina, Tatiana et al. (2006) Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists. J Med Chem 49:2689-702
Besada, Pedro; Mamedova, Liaman; Thomas, Craig J et al. (2005) Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality. Org Biomol Chem 3:2016-25
Jacobson, Kenneth A; Gao, Zhan-Guo; Tchilibon, Susanna et al. (2005) Semi-rational design of (north)-methanocarba nucleosides as dual acting A(1) and A(3) adenosine receptor agonists: novel prototypes for cardioprotection. J Med Chem 48:8103-7
Jacobson, Kenneth A; Ohno, Michihiro; Duong, Heng T et al. (2005) A neoceptor approach to unraveling microscopic interactions between the human A2A adenosine receptor and its agonists. Chem Biol 12:237-47
Van Rompaey, Philippe; Jacobson, Kenneth A; Gross, Ariel S et al. (2005) Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety. Bioorg Med Chem 13:973-83
Lamb, R G; Koch, J C; Snyder, J W et al. (1994) An in vitro model of ethanol-dependent liver cell injury. Hepatology 19:174-82

Showing the most recent 10 out of 14 publications