Garlic and two constituents of garlic, diallyl sulfide (DAS) and diallyl disulfide (DADS), show an ability to regulate transcriptional activity of a number of hepatic enzymes and have the potential to induce herb-drug interactions. Garlic and DAS both cause increased cytochrome P450 (CYP) gene transcription. Garlic and DADS have been shown to increase transcriptional activity of antioxidant enzymes, such as NAD(P)H quinone oxidorecutase (NQO-1), and glutathione S-transferase (GST). While garlic induction of enzymes is well documented, the molecular mechanism(s) that cause these important reactions is not known.
Aim 1 is designed to show that garlic and DAS induce transcriptional regulation of Phase I enzymes by activation of the Constitutive Androstane Receptor (CAR).
Aim 2 is designed to show that garlic and DADS regulate transcription of antioxidant enzymes via activation of the nuclear factor-E2 related factor 2 (Nrf2). CAR activation results in an increase in the quantity of transporters and enzymes responsible for hepatic bilirubin clearance.
Aim 3 is designed to determine whether garlic treatment can increase bilirubin clearance in vivo, and provide an alternative treatment for patients suffering from jaundice and other digestive diseases. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AT002842-02
Application #
7295923
Study Section
Special Emphasis Panel (ZAT1-LD (07))
Program Officer
Moen, Laura K
Project Start
2006-09-29
Project End
2010-09-28
Budget Start
2007-09-29
Budget End
2008-09-28
Support Year
2
Fiscal Year
2007
Total Cost
$35,600
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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
Hardwick, Rhiannon N; Fisher, Craig D; Street, Stephanie M et al. (2012) Molecular mechanism of altered ezetimibe disposition in nonalcoholic steatohepatitis. Drug Metab Dispos 40:450-60
Hardwick, Rhiannon N; Fisher, Craig D; Canet, Mark J et al. (2011) Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease. Drug Metab Dispos 39:2395-402
Lake, April D; Novak, Petr; Fisher, Craig D et al. (2011) Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos 39:1954-60
Hardwick, Rhiannon N; Fisher, Craig D; Canet, Mark J et al. (2010) Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos 38:2293-301
Fisher, Craig D; Lickteig, Andrew J; Augustine, Lisa M et al. (2009) Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease. Drug Metab Dispos 37:2087-94
Fisher, Craig D; Jackson, Jonathan P; Lickteig, Andrew J et al. (2008) Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis. Arch Toxicol 82:959-64