Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold. | Academic Article individual record
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.

author list (cited authors)
Johnson, N. M., Egner, P. A., Baxter, V. K., Sporn, M. B., Wible, R. S., Sutter, T. R., ... Roebuck, B. D.
publication date
2014
published in
keywords
  • DNA Damage
  • Animals
  • Imidazoles
  • Tumor Markers, Biological
  • Male
  • Precancerous Conditions
  • Aflatoxin B1
  • Oligonucleotide Array Sequence Analysis
  • Carcinoma, Hepatocellular
  • Biomarkers, Tumor
  • Rats, Inbred F344
  • Gene Expression Regulation, Neoplastic
  • Glutathione S-Transferase Pi
  • Poisons
  • Oleanolic Acid
  • Gene Expression Profiling
  • Liver Neoplasms, Experimental
  • DNA Adducts
  • Dose-Response Relationship, Drug
  • Rats