The goal of this project is to determine whether pharmacologic induction of Mrp3 can be used as a means of hepatoprotection in humans during cholestatic disease states. Mrp3, which is normally expressed at low levels, serves to export a wide range of organic anions from the liver, back to the blood, thereby decreasing their exposure and toxicity to the liver. Mrp3 expression is significantly increased both in response to certain microsomal enzyme inducers as well as during cholestasis in rodents. Human expression of Mrp3 is also increased in certain liver diseases. Mrp3 expression can be pharmacologically increased by certain microsomal enzyme inducers in both mouse and rat. However, the mechanism for the induction of Mrp3 appears to be a complex interaction where transcriptional studies performed in vitro are unable to accurately replicate the induction observed in vivo.
Aims 1 and 2 are designed to determine whether human Mrp3 expression can be pharmacologically induced by this same mechanism. These are; 1. Determine the common mechanism for the cholestatic and pharmacologic induction of Mrp3 expression. 2. Determine whether the human Mrp3 gene can be induced in vivo using a unique transcriptional activation assay and human liver slices. Cholestasis is a very complex disease with multiple etiologies that results in the accumulation of bile acids and other organic anions that cause profound hepatocellular damage. If Mrp3 can be pharmacologically induced in humans as a means of eliminating hepatic exposure to the toxic effects of accumulating bile acids and other organic anions, this would represent an important means of hepatoprotection during cholestasis.
Aims 3 and 4 have been designed to determine whether Mrp3 induction can be used as a legitimate drug target in the treatment of human liver disease. These are; 3. Determine whether microsomal enzyme inducers that increase expression of Mrp3 are capable of altering the disposition of biliary constituents and protecting against hepatotoxicity during cholestasis. 4. Determine whether the transgenic overexpression of human Mrp3 is hepatoprotective in models of cholestasis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068039-04
Application #
7477795
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Serrano, Jose
Project Start
2005-09-15
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$295,490
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Clarke, John D; Novak, Petr; Lake, April D et al. (2017) Impaired N-linked glycosylation of uptake and efflux transporters in human non-alcoholic fatty liver disease. Liver Int 37:1074-1081
Laho, Tomas; Clarke, John D; Dzierlenga, Anika L et al. (2016) Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir. Biochem Pharmacol 115:144-51
Dzierlenga, Anika L; Clarke, John D; Hargraves, Tiffanie L et al. (2015) Mechanistic basis of altered morphine disposition in nonalcoholic steatohepatitis. J Pharmacol Exp Ther 352:462-70
Canet, Mark J; Merrell, Matthew D; Hardwick, Rhiannon N et al. (2015) Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. Drug Metab Dispos 43:829-35
Clarke, John D; Cherrington, Nathan J (2015) Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability. Pharmacol Ther 151:99-106
Clarke, John D; Novak, Petr; Lake, April D et al. (2014) Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease. Dig Dis Sci 59:365-74
Lake, April D; Novak, Petr; Hardwick, Rhiannon N et al. (2014) The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci 137:26-35
Clarke, John D; Sharapova, Tatiana; Lake, April D et al. (2014) Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis. J Appl Toxicol 34:726-32
Hardwick, Rhiannon N; Ferreira, Daniel W; More, Vijay R et al. (2013) Altered UDP-glucuronosyltransferase and sulfotransferase expression and function during progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos 41:554-61
Lake, April D; Novak, Petr; Shipkova, Petia et al. (2013) Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease. Toxicol Appl Pharmacol 268:132-40

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