Dietary modulation of the biotransformation and genotoxicity of aflatoxin B

• Published in: Toxicology (Amsterdam) 2012-09, Vol.299 (2-3), p.69-79
• Main Authors: Gross-Steinmeyer, Kerstin, Eaton, David L
• Format: Article
• Language: English
• Subjects: aflatoxin B1; Aflatoxin B1 - pharmacokinetics; Aflatoxin B1 - poisoning; Aflatoxin B1 - toxicity; animal models; Animals; antioxidants; Aspergillus flavus; Aspergillus parasiticus; bioavailability; biomarkers; biotransformation; Brassica; carcinogenesis; carcinogens; catalytic activity; chemoprevention; corn; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP3A - metabolism; diet; DNA repair; drug interactions; drugs; enzymes; etiology; foods; gene expression; genotoxicity; hepatocytes; hepatoma; hops; Humans; Inactivation, Metabolic; laboratory animals; Liver Neoplasms - chemically induced; Liver Neoplasms - enzymology; Liver Neoplasms - metabolism; mechanism of action; mutagenicity; Mutagens - metabolism; Mutagens - toxicity; oxidation; peanuts; phytochemicals; pistachios; protective effect; rice; risk factors; secondary metabolites; signal transduction; toxicology; uncertainty; vegetables; vitamins
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2012.05.016

Diet and its various components are consistently identified as among the most important ‘risk factors’ for cancer worldwide, yet great uncertainty remains regarding the relative contribution of nutritive (e.g., vitamins, calories) vs. non-nutritive (e.g., phytochemicals, fiber, contaminants) factors in both cancer induction and cancer prevention. Among the most potent known human dietary carcinogens is the mycotoxin, aflatoxin B₁ (AFB). AFB and related aflatoxins are produced as secondary metabolites by the molds Aspergillus flavus and Aspergillus parasiticus that commonly infect poorly stored foods including peanuts, pistachios, corn, and rice. AFB is a potent hepatocarcinogenic agent in numerous animal species, and has been implicated in the etiology of human hepatocellular carcinoma. Recent research has shown that many diet-derived factors have great potential to influence AFB biotransformation, and some efficiently protect from AFB-induced genotoxicity. One key mode of action for reducing AFB-induced carcinogenesis in experimental animals was shown to be the induction of detoxification enzymes such as certain glutathione-S-transferases that are regulated through the Keap1–Nrf2–ARE signaling pathway. Although initial studies utilized the dithiolthione drug, oltipraz, as a prototypical inducer of antioxidant response, dietary components such as suforaphane (SFN) are also effective inducers of this pathway in rodent models. However, human GSTs in general do not appear to be extensively induced by SFN, and GSTM1 – the only human GST with measurable catalytic activity toward aflatoxin B₁-8,9-epoxide (AFBO; the genotoxic metabolite of AFB), does not appear to be induced by SFN, at least in human hepatocytes, even though its expression in human liver cells does appear to offer considerable protection against AFB–DNA damage. Although induction of detoxification pathways has served as the primary mechanistic focus of chemoprevention studies, protective effects of chemoprotective dietary components may also arise through a decrease in the rate of activation of AFB to AFBO. Dietary consumption of apiaceous vegetables inhibits CYP1A2 activity in humans, and it has been demonstrated that some compounds in those vegetables act as potent inhibitors of human CYP1A2 and cause reduced hCYP1A2-mediated mutagenicity of AFB. Other dietary compounds of different origin (e.g., constituents of brassica vegetables and hops) have been shown to modify expression of human hepatic