Drug toxicity is the number one cause of acute liver failure, and hepatotoxicity is the most common reason why drugs are withdrawn from the US market or are stopped from clinical development. Interestingly, studies in rodents show that the liver acquires resistance to chemical injury following sub-lethal administration of hepatotoxicants such as acetaminophen (APAP) and carbon tetrachloride (CCl4). Similar tolerance is seen in a subset of human patients that use APAP. Currently, the mechanism of this resiliency is not known. It likely involves compensatory changes in response to oxidative and inflammatory signals triggered by hepatotoxicant exposure. A better understanding of this phenomenon is important since it may represent a source of clinically relevant drug-disease interactions in individuals with acute liver injury. Changes in transport protein-mediated influx and efflux of xenobiotics could contribute to hepatotoxicant resistance. Preliminary data from this laboratory show significant changes in gene and protein expression for a number of multidrug resistance proteins (Mrps) in mice receiving APAP and CCI4 treatment. We hypothesized that changes in expression of Mrp transporters during chemical-induced liver injury is a compensatory mechanism by which hepatocytes acquire resistance to subsequent hepatotoxicant challenge. We propose to test this hypothesis by first, investigating the temporal and zonal changes in expression and localization of hepatic Mrps following APAP and CCI4 treatment. Then, we will determine if inflammatory mediators contribute to this response by modulating cellular sources of cytokines. The final experiments will examine the role of the transcription factor-E2 p45-related factor 2 (Nrf2) in regulating transporter gene expression in mice lacking Nrf2 during injury and recovery from APAP and CC4 treatment. Nrf2 coordinately regulates the expression of drug metabolizing and detoxification genes. Its role in regulating Mrps has not been investigated. The proposed studies are expected to demonstrate that changes in liver transport protein expression following hepatotoxicant exposure represent an adaptation process that prevents accumulation of certain chemicals. This adaptive response may be essential for hepatocyte survival during periods of injury and regeneration. A comprehensive characterization of transport protein expression under the experimental conditions described in the proposal is of great relevance to human health. This information should give us an indication of the potential susceptibility of individuals with acute liver injury to pharmaceuticals that: a.) require transporter function for their excretion from the liver, and/or b). generate mediators of inflammation and injury that can be eliminated via transporter action.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069557-02
Application #
7125073
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Serrano, Jose
Project Start
2005-09-30
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$256,780
Indirect Cost
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Flores, Katiria; Manautou, José E; Renfro, J Larry (2017) Gender-specific expression of ATP-binding cassette (Abc) transporters and cytoprotective genes in mouse choroid plexus. Toxicology 386:84-92
Scialis, Renato J; Manautou, José E (2016) Elucidation of the Mechanisms through Which the Reactive Metabolite Diclofenac Acyl Glucuronide Can Mediate Toxicity. J Pharmacol Exp Ther 357:167-76
Rigalli, Juan Pablo; Perdomo, Virginia Gabriela; Ciriaci, Nadia et al. (2016) The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2). Toxicol Appl Pharmacol 304:90-8
Ghanem, Carolina I; Pérez, María J; Manautou, José E et al. (2016) Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. Pharmacol Res 109:119-31
Ferreira, Daniel W; Goedken, Michael J; Rommelaere, Samuel et al. (2016) Enhanced hepatotoxicity by acetaminophen in Vanin-1 knockout mice is associated with deficient proliferative and immune responses. Biochim Biophys Acta 1862:662-669
Rudraiah, Swetha; Gu, Xinsheng; Hines, Ronald N et al. (2016) Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells. Toxicol In Vitro 31:54-9
Scialis, Renato J; Csanaky, Iván L; Goedken, Michael J et al. (2015) Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac. Drug Metab Dispos 43:944-50
Njayou, Frédéric Nico; Amougou, Atsama Marie; Fouemene Tsayem, Romeo et al. (2015) Antioxidant fractions of Khaya grandifoliola C.DC. and Entada africana Guill. et Perr. induce nuclear translocation of Nrf2 in HC-04 cells. Cell Stress Chaperones 20:991-1000
Ghanem, Carolina I; Rudraiah, Swetha; Bataille, Amy M et al. (2015) Role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the transcriptional regulation of brain ABC transporters during acute acetaminophen (APAP) intoxication in mice. Biochem Pharmacol 94:203-11
O'Connor, Meeghan A; Koza-Taylor, Petra; Campion, Sarah N et al. (2014) Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection). Toxicol Appl Pharmacol 274:156-67

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