DNA damage by mycotoxins

Mycotoxins are toxic fungal metabolites which are structurally diverse, com mon contaminants of the ingredients of animal feed and human food. To date, mycotoxins with carcinogenic potency in experimental animal models include aflatoxins, sterigmatocystin, ochratoxin, fumonisins, zearalenone, and som e Penicillium toxins. Most of these carcinogenic mycotoxins are genotoxic a gents with the exception of fumonisins, which is currently believed to act by disrupting the signal transduction pathways of the target cells. Aflatox in B-1 (AFB(1)), a category I known human carcinogen and the most potent ge notoxic agent, is mutagenic in many model systems and produces chromosomal aberrations, micronuclei, sister chromatid exchange, unscheduled DNA synthe sis, and chromosomal strand breaks, as well as forms adducts in rodent and human cells. The predominant AFB(1)-DNA adduct was identified as 8,9-dihydr o-8-(N-7-guanyl)-9-hydroxy-AFB(1) (AFB(1)-N-7-Gua), which derives from cova lent bond formation between C8 of AFB(1)-8,9-epoxides and N-7 Of guanine ba ses in DNA. Initial AFB(1)-N-7-guanine adduct convert to a ring-opened form amidopyrimidine derivative; AFB(1)-FAPY. The formation of AFB(1)-N-7-guanin e adduct was linear over the low-dose range in all species examined, and li ver, the primary target organ, had the highest level of the adduct. Formati on of initial AFB(1)-N-7-guanine adduct was correlated with the incidence o f hepatic tumor in trout and rats. The AFB(1)-N-7-guanine adduct was remove d from DNA rapidly and was excreted exclusively in urine of exposed rats. S everal human studies have validated the similar correlation between dietary exposure to AFB(1) and excretion of AFB(1)-N-7-guanine in urine. Replicati on of DNA containing AFB(1)-N-7-guanine adduct-induced G --> T mutations in an experimental model. Activation of ms protooncogene has been found in AF B(1)-induced tumors in mouse, rat, and fish. More strikingly, the relations hip between aflatoxin exposure and development of human hepatocellular carc inoma (HHC) was demonstrated by the studies on the p53 tumor suppressor gen e. High frequency of p53 mutations (G -->T transversion at codon 249) was f ound to occur in HHC collected from populations exposed to high levels of d ietary aflatoxin in China and Southern Africa. Furthermore, AFB(1)-induced DNA damage and hepatocarcinogenesis in experimental models can be modulated by a variety of factors including nutrients, chemopreventive agents, and o ther factors such as food restriction and viral infection, as well as genet ic polymorphisms. (C) 1999 Elsevier Science B.V. All rights reserved.