Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes.

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Research Abstract Details 

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Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Abstract Text:

Melinda S Yates,Masafumi Tauchi,Fumiki Katsuoka,Kathleen C Flanders,Karen T Liby,Tadashi Honda,Gordon W Gribble,Delinda A Johnson,Jeffrey A Johnson,Neal C Burton, Guilarte,Masayuki Yamamoto,Michael B Sporn,Thomas W Kensler,

Synthetic triterpenoids have been developed, which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving on the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-antioxidant response element (ARE) signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces ARE-regulated cytoprotective genes in many tissues in the mouse, including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 mumol/kg body weight (orally). A structure activity evaluation of 15 additional triterpenoids (a) confirmed the importance of Michael acceptor groups on both the A and C rings, (b) showed the requirement for a nitrile group at C-2 of the A ring, and (c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester CDDO-Me (TP155) and the dinitrile TP225, are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs.

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Publishing Authors By Initials

MS Yates,M Tauchi,F Katsuoka,KC Flanders,KT Liby,T Honda,GW Gribble,DA Johnson,JA Johnson,NC Burton,TR Guilarte,M Yamamoto,MB Sporn,TW Kensler,

For similar organic chemicals: hydrocarbons: terpenes: triterpenes research abstracts see: organic chemicals: hydrocarbons: terpenes: triterpenes research

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Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular cancer therapeutics

VOLUME: 6

Page Numbers: 154-62

Journal Abbreviation: Mol. Cancer Ther.

ISSN: 1535-7163

DAY: 3

MONTH: Jan

YEAR: 2007

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101132535

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Keywords Mesh Terms:

KEYWORDS: Triterpenes

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Information

Substance Name: Nqo1 protein, mouse

Registry Number: EC 1.6.99.1.

Grant and Affiliation Information for Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes.

AFFILIATION: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Room E7541, 615 North Wolfe Street, Baltimore, MD 21205, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: T32 GM08763

ACRONYM: GM

MEDLINETA: Mol Cancer Ther

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