title: Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold.
abstract: In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P-positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200 μg/kg rat/day) for four weeks and receiving either vehicle or CDDO-Im (three times weekly), one week before and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared with a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N(7)-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P-positive foci increased substantially (0%-13.8%) over the four weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im-treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development.
authors.affiliation: Authors' Affiliations: Department of Environmental Health Sciences, Bloomberg School of Public Health;
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Johnson
authors.affiliation: Authors' Affiliations: Department of Environmental Health Sciences, Bloomberg School of Public Health;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Egner
authors.affiliation: Department of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland;
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Baxter
authors.affiliation: Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire;
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.affiliation: W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee; and.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Wible
authors.affiliation: W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee; and.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sutter
authors.affiliation: Authors' Affiliations: Department of Environmental Health Sciences, Bloomberg School of Public Health;
authors.forename: John D
authors.initials: JD
authors.lastname: Groopman
authors.affiliation: Authors' Affiliations: Department of Environmental Health Sciences, Bloomberg School of Public Health; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; Bill.D.Roebuck@dartmouth.edu.
authors.forename: Bill D
authors.initials: BD
authors.lastname: Roebuck
mesh_terms: D016604:Aflatoxin B1 / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D007093:Imidazoles / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D011042:Poisons / Q000633:toxicity; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D014408:Biomarkers, Tumor; D018736:DNA Adducts; D007093:Imidazoles; D011042:Poisons; C072611:aflatoxin B1-DNA adduct; D009828:Oleanolic Acid; D016604:Aflatoxin B1; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat