Mechanisms of Aflatoxin Carcinogenesis

Abstract

Much progress has been made in elucidating the biochemical and molecular mechanisms that underlie aflatoxin carcinogenesis. In humans, biotransformation of AFB1 to the putative carcinogenic intermediate. AFB-8,9-exo-epoxide, occurs predominantly by cytochromes P450 1A2 and 3A4, with the relative importance of each dependent upon the relative magnitude of expression of the respective enzymes in liver. Genetic variability in the expression of these and other cytochromes P450 may result in substantial interindividual differences in susceptibility to the carcinogenic effects of aflatoxins. Detoxification of AFB-8,9-epoxide by a specific alpha class glutathione S-transferase is an important protective mechanism in mice, and it accounts for the resistance of this species to the carcinogenic effects of AFB. This particular form of GST is expressed constitutively only at low levels in rats, but it is inducible by antioxidants such as ethoxyquin, and it accounts for much of the chemoprotective effects of a variety of substances, including natural dietary components that putatively act via an "antioxidant response element" (ARE). In humans, the constitutively expressed GSTs have very little activity toward AFB1-8,9-exo-epoxide, suggesting that--on a biochemical basis--humans should be quite sensitive to the genotoxic effects of aflatoxins. If a gene encoding a high aflatoxin-active form of GST is present in the human genome, but is not constitutively expressed, and is inducible by dietary antioxidants (as occurs in rats), then chemo- and/or dietary intervention measures aimed at inducing this enzyme could be highly effective. However, as it is possible that human CYP 1A2 may also be inducible by these same chemicals (because of the possible presence of an ARE in this gene), the ultimate consequence of dietary treatment with chemicals that induce biotransformation enzymes via an ARE is uncertain. The balance of the rate of activation (exo-epoxide production) to inactivation (GST conjugation plus other P450-mediated non-epoxide oxidations) may be a strong indicator of individual and species susceptibility to aflatoxin carcinogenesis, if the experimental conditions are reflective of true dietary exposures. There is strong evidence that AFB-8,9-exo-epoxide binds to G:C rich regions of DNA, forming an adduct at the N7-position of guanine. Substantial evidence demonstrates that AFB1-8,9-epoxide can induce activating mutations in the ras oncogene in experimental animals, primarily at codon 12.(ABSTRACT TRUNCATED AT 400 WORDS)

Determination of levels of polycyclic aromatic hydrocarbons in soil contaminated with spent motor Engine oil in Abakaliki Auto-Mechanic Village

“…This disrupts the normal process of copying DNA and induces mutations. This explains the occurrence of cancer after exposure (Eaton and Gallagher, 1994). Research also indicated that benzo[a]pyrene diol epoxide specifically targets and destroys the protective gene thereby leading to cancer (Pfeifer et al, 2002;Daniel, 2007).…”

Variation in the Occurence of Aflatoxins in Various Processed Forms of Dried Ginger

“…When reduced to the ground form, it is used as an ingredient in various spice blends and in the food processing industry. Aflatoxins (AFs) are secondary metabolites which are of great concern because of their detrimental effects on human and animal health, including carcinogenic, mutagenic, teratogenic, and immunosuppressive effects (Eaton & Gallagher, 1994), aflatoxins B1, B2, G1 and G2 are normally found in foods (Wogan et al, 2012). They are produced mainly by three species of Aspergillus: Aspergillus flavus, Aspergillus parasiticus and Aspergillus nomius, and can occur in a wide range of important raw food commodities including spices, cereals, nuts, figs and dried fruits.…”

Isolation and Characterization of the Versicolorin B Synthase Gene from Aspergillus parasiticus

“…Depurination of the alkylated base has been correlated to bladder cancer in laboratory mice (8 -10), teratogenic effects in chicken embryos (11), and liver cancer in humans (12)(13)(14). A direct connection between DNA damage and the incidence of human cancer has been established to originate at mutational hot spots of the p53 gene, a tumor suppressor gene whose altered sequence has been associated with approximately 50% of all human cancers (15,16). Aflatoxin B 1 has been found to be responsible in particular for G 3 T transversions at codon 249 of the p53 tumor suppressor gene in hepatocarcinogenesis (17,18) (Scheme I).…”