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DNA damage by mycotoxins.

J S Wang1, J D Groopman

  • 1Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

Mutation Research
|March 5, 1999
PubMed
Summary

Aflatoxin B1 (AFB1) is a potent carcinogen that forms DNA adducts, leading to mutations and cancer. AFB1 exposure correlates with liver cancer, particularly hepatocellular carcinoma (HHC), and p53 gene mutations in humans.

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Area of Science:

  • Toxicology
  • Carcinogenesis
  • Molecular Biology

Background:

  • Mycotoxins are toxic fungal metabolites contaminating food and feed.
  • Several mycotoxins, including aflatoxins, exhibit carcinogenic potential in animal models.
  • Aflatoxin B1 (AFB1) is a known human carcinogen and a potent genotoxic agent.

Purpose of the Study:

  • To investigate the genotoxic mechanisms of AFB1, focusing on DNA adduct formation and mutations.
  • To explore the correlation between AFB1 exposure, DNA adducts, and the development of cancer, specifically hepatocellular carcinoma (HHC).
  • To examine the role of the p53 tumor suppressor gene in AFB1-induced hepatocarcinogenesis.

Main Methods:

  • Identification and characterization of AFB1-DNA adducts, primarily AFB1-N7-guanine.
  • Dose-response studies on AFB1-N7-guanine adduct formation and excretion in experimental models.
  • Analysis of mutations in oncogenes (ras) and tumor suppressor genes (p53) in AFB1-induced tumors.
  • Epidemiological studies correlating dietary AFB1 exposure with HHC incidence and p53 mutations.

Main Results:

  • The predominant AFB1-DNA adduct, AFB1-N7-guanine, forms linearly with dose and is highest in the liver.
  • AFB1-N7-guanine adduct formation correlates with hepatic tumor incidence in rodents and fish.
  • A high frequency of p53 mutations (G-->T transversion at codon 249) is observed in HHC from populations with high AFB1 exposure.
  • AFB1-induced DNA damage and cancer can be modulated by nutrients, chemopreventive agents, and genetic factors.

Conclusions:

  • AFB1 is a significant etiological agent for human hepatocellular carcinoma (HHC) through its genotoxic and mutagenic effects.
  • The formation and persistence of AFB1-DNA adducts, particularly AFB1-N7-guanine, are critical steps in AFB1-induced carcinogenesis.
  • Targeted mutations in the p53 tumor suppressor gene are a hallmark of AFB1-induced HHC, highlighting its role in cancer development.

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