Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole.
Synthetic triterpenoid analogues of oleanolic acid are potent inducers of the phase 2 response as well as inhibitors of inflammation. We show that the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), is a highly potent chemopreventive agent that inhibits aflatoxin-induced tumorigenesis in rat liver. The chemopreventive potency of CDDO-Im was evaluated by measuring inhibition of formation of putative preneoplastic lesions (glutathione S-transferase P positive foci) in the liver of rats exposed to aflatoxin B1. CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 micromol/kg body weight and a >99% reduction at 100 micromol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by approximately 40% to 90% over the range of 1 to 100 micromol/kg body weight. Additionally, changes in mRNA levels of genes involved in aflatoxin metabolism were measured in rat liver following a single dose of CDDO-Im. GSTA2, GSTA5, AFAR, and EPHX1 transcripts are elevated 6 hours following a 1 micromol/kg body weight dose of CDDO-Im. Microarray analysis using wild-type and Nrf2 knockout mice confirms that many phase 2 and antioxidant genes are induced in an Nrf2-dependent manner in mouse liver following treatment with CDDO-Im. Thus, low-micromole doses of CDDO-Im induce cytoprotective genes, inhibit DNA adduct formation, and dramatically block hepatic tumorigenesis. As a point of reference, oltipraz, an established modulator of aflatoxin metabolism in humans, is 100-fold weaker than CDDO-Im in this rat antitumorigenesis model. The unparalleled potency of CDDO-Im in vivo highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids.
Yates
Melinda S
MS
Johns Hopkins University, Baltimore, Maryland, USA.
Kwak
Mi-Kyoung
MK
Egner
Patricia A
PA
Groopman
John D
JD
Bodreddigari
Sridevi
S
Sutter
Thomas R
TR
Baumgartner
Karen J
KJ
Roebuck
B D
BD
Liby
Karen T
KT
Yore
Mark M
MM
Honda
Tadashi
T
Gribble
Gordon W
GW
Sporn
Michael B
MB
Kensler
Thomas W
TW
D016604:Aflatoxin B1 / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C072611:aflatoxin B1-DNA adduct; D009828:Oleanolic Acid; D016604:Aflatoxin B1