""""""""Drug idiosyncrasy"""""""" refers to a toxic response to a drug that occurs in a small fraction of people and bears no obvious relationship to dosing regimen. Numerous drugs developed for various therapeutic purposes have produced in people idiosyncratic responses that have resulted in serious injury to liver and other organs. These reactions typically do not become apparent in preclinical animal studies, and little is understood about underlying mechanisms. Animal models with the potential to enable prediction/early identification of idiosyncratic responses could prevent human suffering and lead to understanding of mechanisms. In preliminary studies, we have found in rats that modest inflammation produced by a small, nontoxic dose of endotoxin (LPS) can render an otherwise nonhepatotoxic drug hepatotoxic. For example, in rats given a nontoxic dose of chlorpromazine, co treatment with a small dose of LPS resulted in liver injury and elevated plasma creatine kinase activity, two responses that occur idiosyncratically in people during therapy with this and related drugs. Similarly, a nontoxic dose of LPS; can render ranitidine hepatotoxic in rats and mice. These preliminary results suggest a novel mechanism for drug idiosyncrasy and raise the possibility of creating useful animal models for such responses in humans. The hypothesis to be tested is that idiosyncratic drug reactions that occur in humans can be reproduced in animals by drug administration during a concurrent episode of mild inflammation. Several drugs that have caused idiosyncratic liver injury in humans (chlorpromazine, ranitidine, flutamide) and two that have not (promethazine, famotidine) will be used. Rats will be co exposed to a drug and to a dose of LPS that causes """"""""modest inflammatory response"""""""" to determine if the co treatment reproduces the idiosyncratic drug responses that people experience. Dose-response and temporal relationships will be defined. Inflammatory factors (e.g. neutrophils, tumor necrosis factor-alpha, cyclooxygenase 2) likely to be critical to the toxic response will be evaluated. In addition, a cell-based, in vitro system will be developed and used to explore intracellular signaling mechanisms that enable drugs to interact with inflammatory factors to result in synergistic hepatocyte killing. Results from these studies will be an important step toward creating predictive animal models of human drugs idiosyncrasy and exploring underlying mechanisms. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061315-02
Application #
6798348
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Serrano, Jose
Project Start
2003-09-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$231,726
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Maiuri, Ashley R; Breier, Anna B; Turkus, Jonathan D et al. (2016) Calcium Contributes to the Cytotoxic Interaction Between Diclofenac and Cytokines. Toxicol Sci 149:372-84
Beggs, Kevin M; Maiuri, Ashley R; Fullerton, Aaron M et al. (2015) Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related. Toxicology 331:35-46
Poulsen, Kyle L; Olivero-Verbel, Jesus; Beggs, Kevin M et al. (2014) Trovafloxacin enhances lipopolysaccharide-stimulated production of tumor necrosis factor-? by macrophages: role of the DNA damage response. J Pharmacol Exp Ther 350:164-70
Poulsen, Kyle L; Albee, Ryan P; Ganey, Patricia E et al. (2014) Trovafloxacin potentiation of lipopolysaccharide-induced tumor necrosis factor release from RAW 264.7 cells requires extracellular signal-regulated kinase and c-Jun N-Terminal Kinase. J Pharmacol Exp Ther 349:185-91
Beggs, Kevin M; Fullerton, Aaron M; Miyakawa, Kazuhisa et al. (2014) Molecular mechanisms of hepatocellular apoptosis induced by trovafloxacin-tumor necrosis factor-alpha interaction. Toxicol Sci 137:91-101
Lu, Jingtao; Roth, Robert A; Malle, Ernst et al. (2013) Roles of the hemostatic system and neutrophils in liver injury from co-exposure to amiodarone and lipopolysaccharide. Toxicol Sci 136:51-62
Lu, Jingtao; Miyakawa, Kazuhisa; Roth, Robert A et al. (2013) Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress. Toxicol Sci 131:164-78
Lu, Jingtao; Jones, A Daniel; Harkema, Jack R et al. (2012) Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha. Toxicol Sci 125:126-33
Zou, Wei; Roth, Robert A; Younis, Husam S et al. (2011) Neutrophil-cytokine interactions in a rat model of sulindac-induced idiosyncratic liver injury. Toxicology 290:278-85
Dugan, Christine M; Fullerton, Aaron M; Roth, Robert A et al. (2011) Natural killer cells mediate severe liver injury in a murine model of halothane hepatitis. Toxicol Sci 120:507-18

Showing the most recent 10 out of 37 publications