Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Dose Response Group, Society of Risk Assessment: Webinar (noon EST, Tuesday, 5 April 16) Complete Protection against Aflatoxin B1-Induced Liver Cancer with a Triterpenoid: DNA Adduct Dosimetry and Genotoxicity Threshold Bill D. Roebuck1, John D. Groopman2, and Thomas W. Kensler2,3 1 Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire Department of Environmental Health Sciences, Bloomberg School of Public Health, Baltimore, Maryland 3 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 2 In the early 1960s, aflatoxins were discovered in food grains and shown to be both acutely toxic and to cause liver cancer. Aflatoxins are produced by molds (such as, Aspergillus flavus) widely occurring on crops such as maize (corn) and groundnuts (peanuts) and they are found in foods produced from these crops. In high exposures (mg/kg body weight), aflatoxins cause acute toxicity particularly to the liver with growth retardation and death depending upon the dose and duration of aflatoxin exposure. With lower exposures (µg/kg) of aflatoxins (particularly aflatoxin B1; AFB1) in a wide variety of domestic and livestock animals as well as a wide array of experimental species, aflatoxins cause liver diseases including hepatocellular cancer (HCC). Mold growth and aflatoxin production can be controlled by a variety of pre- and post-harvest agricultural practices, but not completely eliminated. Worldwide HCC is the second leading cause of cancer deaths. We have been interested in using chemicals some of which are approved drugs, to block, retard, or reverse carcinogenic processes, a strategy termed cancer chemoprevention. Our work was facilitated by the development of highly reproducible and quantitative rat models of liver carcinogenesis. In this setting, the antischistosomal drug oltipraz produced marked reductions in incidence of HCC from 20 to 0% with low doses of AFB1 and 83 to 48% with AFB1 at higher doses and longer duration of exposure. In both experiments, significant, but incomplete reduction of hepatic aflatoxin-derived DNA adducts were observed in parallel cohorts of rats. Reduction in levels of hepatic DNA adducts underestimated the efficacy of the chemopreventive intervention, suggesting a background of adducts not aligned with risk of HCC. This presentation focuses on the same AFB1-rat model, but with a new generation of cancer chemoprevention agents. 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 mg/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. 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, the integrated level of urinary AFB1-N7-guanine was significantly reduced (66%) and aflatoxin-Nacetylcysteine, 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-week dosing period, but was largely absent with CDDO-Im intervention. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin DNA adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development. ___________________ * Johnson NM, Egner PA, Baxter VK, Sporn MB, Wible RS, Sutter TR, Groopman JD, Kensler TW, Roebuck BD. Complete protection against aflatoxin B(1)-induced liver cancer with a triterpenoid: DNA adduct dosimetry, molecular signature, and genotoxicity threshold. Cancer Prev Res (Phila) 2014; 7(7):658-65.