The potent anticarcinogenic effects of phenolic antioxidants 2(3)-tert- butyl-4-hydroxyanisole (BHA), and its demethylated active metabolite 2(3)-tert-butylhydroquinone (tBHQ), are partly attributed to potent induction of some phase 2 drug metabolizing enzymes such as glutathione S-transferases (GST), NAD(P)H: quinone oxidoreductases (NQO) and UDP-glucuronosyltransferases (UGT). However, the molecular mechanisms by which BHA and tBHQ induce phase 2 detoxifying enzymes, a potential chemopreventive action, have not been characterized. Recent studies from our laboratory and others have shown that the activity of a cellular signaling molecules, the mitogen-activated protein kinases (MAPKs), extracellular regulated kinase 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1), or p38 can be enhanced by BHA and tBHQ, in a time- and dose-dependent fashion. The observations that modulation of one or more of these MAP kinase pathways by genetic or biochemical approaches, altered the level of expression of phase 2 NQO enzyme activity led us to propose the hypothesis that phenolic compounds such as BHA induce MAPK signaling pathway leading to phase 2 gene induction. The following specific aims are designed to test this hypothesis. (1) Determine the dose-dependent effect of BHA administration on the in vivo activation of MAPK and induction of phase 2 genes expression in mouse livers. (2) Determine the activation of MAPK pathways in hepatoma cell lines and in primary cultured of human and mouse hepatocytes in BHA-induced phase 2 NQO gene induction. (3) Determine the activation of transcription factor Nrf2 by MAPK pathways in BHA-induced phase 2 NQO gene induction. (4) Determine the phosphorylation of Nrf2 in BHA-induced phase 2 NQO gene induction. The results of our work will likely provide new information on (i) the role of signal transduction events in the regulation of phase 2 NQO gene expression by phenolic antioxidants such as BHA, and (ii) identification of the signaling pathway components that can be useful as chemopreventive agent design and screening targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094828-05
Application #
6880079
Study Section
Special Emphasis Panel (ZRG1-ET-2 (03))
Program Officer
Crowell, James A
Project Start
2001-06-11
Project End
2007-04-12
Budget Start
2005-05-01
Budget End
2007-04-12
Support Year
5
Fiscal Year
2005
Total Cost
$283,187
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Kim, Jung-Hwan; Xu, Eugenia Y; Sacks, David B et al. (2013) Identification and functional studies of a new Nrf2 partner IQGAP1: a critical role in the stability and transactivation of Nrf2. Antioxid Redox Signal 19:89-101
Kim, J-H; Yu, S; Chen, J D et al. (2013) The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains. Oncogene 32:514-27
Su, Zheng-Yuan; Shu, Limin; Khor, Tin Oo et al. (2013) A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem 329:133-62
Lee, Jong Hun; Khor, Tin Oo; Shu, Limin et al. (2013) Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression. Pharmacol Ther 137:153-71
Wang, Hu; Khor, Tin Oo; Yang, Qian et al. (2012) Pharmacokinetics and pharmacodynamics of phase II drug metabolizing/antioxidant enzymes gene response by anticancer agent sulforaphane in rat lymphocytes. Mol Pharm 9:2819-27
Lin, Wen; Hong, Jin-Liern; Shen, Guoxiang et al. (2011) Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition. Biopharm Drug Dispos 32:65-75
Saw, Constance L; Huang, Mou-Tuan; Liu, Yue et al. (2011) Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol Carcinog 50:479-86
Saw, Constance Lay-Lay; Cintrón, Melvilí; Wu, Tien-Yuan et al. (2011) Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. Biopharm Drug Dispos 32:289-300
Wu, Tien-Yuan; Khor, Tin Oo; Saw, Constance Lay Lay et al. (2011) Anti-inflammatory/Anti-oxidative stress activities and differential regulation of Nrf2-mediated genes by non-polar fractions of tea Chrysanthemum zawadskii and licorice Glycyrrhiza uralensis. AAPS J 13:1-13
Swanson, Hollie I; Njar, Vincent C O; Yu, Zhen et al. (2010) Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy. Drug Metab Dispos 38:539-44

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