Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes.
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.
Yates
Melinda S
MS
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Room E7541, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Tauchi
Masafumi
M
Katsuoka
Fumiki
F
Flanders
Kathleen C
KC
Liby
Karen T
KT
Honda
Tadashi
T
Gribble
Gordon W
GW
Johnson
Delinda A
DA
Johnson
Jeffrey A
JA
Burton
Neal C
NC
Guilarte
Tomás R
TR
Yamamoto
Masayuki
M
Sporn
Michael B
MB
Kensler
Thomas W
TW
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D018890:Chemoprevention; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D007093:Imidazoles / Q000737:chemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000975:Antioxidants; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D014315:Triterpenes; D009828:Oleanolic Acid; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase