Of Mice, Rats, and Men: Could Nrf2 Activation Protect against Aflatoxin Heptocarcinogenesis in Humans?

Abstract

In this issue, Johnson and colleagues provide a remarkable demonstration of the potential for "chemoprevention" of cancer from mutagenic chemicals. The authors demonstrated complete protection of rats from a carcinogenic treatment regimen with the potent dietary mutagen and hepatocarcinogen, aflatoxin B1 (AFB) by pretreatment with a synthetic oleanane triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). This study is notable for two reasons: (i) Activation of the Nrf2/Keap1/ARE "antioxidant response" pathway by CDDO-Im conferred complete protection against AFB-induced hepatocellular carcinomas in the Fisher F344 rat (a strain frequently used in life-time carcinogenicity bioassays), and (ii) extensive AFB-DNA adduct formation was seen in all animals at early time points, including those treated with CDDO-Im, albeit at lower levels (∼30% of the untreated animals), suggesting a strong divergence in the association between early DNA-damaging events, and tumor formation later in life. The authors suggest that this provides compelling experimental support for the concept of carcinogenic "thresholds" for mutagenic chemicals, because the treatment reduced persistent, mutagenic adducts (AFB-FAPyr adducts) only by 70%, but nearly completely eliminated tumors after approximately 2 years and preneoplastic lesions 6 weeks after the last dose of AFB.