DNA damage by mycotoxins

Mycotoxins are toxic fungal metabolites which are structurally diverse, common 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 some Penicillium toxins. Most of these carcinogenic mycotoxins are genotoxic agents with the exception of fumonisins, which is currently believed to act by disrupting the signal transduction pathways of the target cells. Aflatoxin B-1 (AFB(1)), a category I known human carcinogen and the most potent genotoxic agent, is mutagenic in many model systems and produces chromosomal aberrations, micronuclei, sister chromatid exchange, unscheduled DNA synthesis, 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-dihydro-8-(N-7-guanyl)-9-hydroxy-AFB(1) (AFB(1)-N-7-Gua), which derives from covalent bond formation between C8 of AFB(1)-8,9-epoxides and N-7 Of guanine bases in DNA. Initial AFB(1)-N-7-guanine adduct convert to a ring-opened formamidopyrimidine derivative; AFB(1)-FAPY. The formation of AFB(1)-N-7-guanine adduct was linear over the low-dose range in all species examined, and liver, the primary target organ, had the highest level of the adduct. Formation of initial AFB(1)-N-7-guanine adduct was correlated with the incidence of hepatic tumor in trout and rats. The AFB(1)-N-7-guanine adduct was removed from DNA rapidly and was excreted exclusively in urine of exposed rats. Several human studies have validated the similar correlation between dietary exposure to AFB(1) and excretion of AFB(1)-N-7-guanine in urine. Replication 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 AFB(1)-induced tumors in mouse, rat, and fish. More strikingly, the relationship between aflatoxin exposure and development of human hepatocellular carcinoma (HHC) was demonstrated by the studies on the p53 tumor suppressor gene. High frequency of p53 mutations (G -->T transversion at codon 249) was found to occur in HHC collected from populations exposed to high levels of dietary 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 other factors such as food restriction and viral infection, as well as genetic polymorphisms. (C) 1999 Elsevier Science B.V. All rights reserved.