Susceptibility to aflatoxin B1-induced carcinogenesis correlates with tissue-specific differences in DNA repair activity in mouse and in rat

Cancer Res. 2005 Feb 15;65(4):1265-70. doi: 10.1158/0008-5472.CAN-04-3373.

Abstract

To investigate the mechanisms responsible for species- and tissue-specific differences in susceptibility to aflatoxin B(1) (AFB(1))-induced carcinogenesis, DNA repair activities of nuclear extracts from whole mouse lung and liver and rat liver were compared, and the ability of in vivo treatment of mice with AFB(1) to alter repair of AFB(1)-DNA damage was determined. Plasmid DNA containing AFB(1)-N(7)-guanine or AFB(1)-formamidopyrimidine adducts were used as substrates for the in vitro determination of DNA repair synthesis activity, detected as incorporation of radiolabeled nucleotides. Liver extracts from CD-1 mice repaired AFB(1)-N(7)-guanine and AFB(1)-formamidopyrimidine adducts 5- and 30-fold more effectively than did mouse lung, and approximately 6- and 4-fold more effectively than did liver extracts from Sprague-Dawley rats. The susceptibility of mouse lung and rat liver to AFB(1)-induced carcinogenesis correlated with lower DNA repair activity of these tissues relative to mouse liver. Lung extracts prepared from mice treated with a single tumorigenic dose of 50 mg/kg AFB(1) i.p. and euthanized 2 hours post-dosing showed minimal incision and repair synthesis activities relative to extracts from vehicle-treated mice. Conversely, repair activity towards AFB(1)-N(7)-guanine damage was approximately 3.5-fold higher in liver of AFB(1)-treated mice relative to control. This is the first study to show that in vivo treatment with AFB(1) can lead to a tissue-specific induction in DNA repair. The results suggest that lower DNA repair activity, sensitivity of mouse lung to inhibition by AFB(1), and selective induction of repair in liver contribute to the susceptibility of mice to AFB(1)-induced lung tumorigenesis relative to hepatocarcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aflatoxin B1 / analogs & derivatives*
  • Aflatoxin B1 / metabolism
  • Aflatoxin B1 / toxicity*
  • Animals
  • Carcinogens / toxicity
  • Cocarcinogenesis*
  • DNA / drug effects
  • DNA / metabolism
  • DNA Repair / physiology*
  • Female
  • Genetic Predisposition to Disease
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver / physiology
  • Liver Neoplasms / chemically induced*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / physiology
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Male
  • Mice
  • Pyrimidines / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity

Substances

  • Carcinogens
  • Pyrimidines
  • Guanine
  • 2,3-dihydro-2-(N(7)-guanyl)-3-hydroxyaflatoxin B1
  • aflatoxin B1-formamidopyrimidine
  • DNA
  • Aflatoxin B1