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Susceptibility to Aflatoxin B₁-Induced Carcinogenesis Correlates with Tissue-Specific Differences in DNA Repair Activity in Mouse and in Rat

Departments of ¹ Pharmacology and Toxicology, ² Chemistry and ³ Cancer Research Laboratories, Queen's University, Kingston, Ontario, Canada

Requests for reprints: Thomas E. Massey, Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada K7L 3N6. Phone: 613-533-6115; Fax: 613-533-6412; E-mail: masseyt{at}post.queensu.ca.

To investigate the mechanisms responsible for species- and tissue-specific differences in susceptibility to aflatoxin B₁ (AFB₁)–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 AFB₁ to alter repair of AFB₁-DNA damage was determined. Plasmid DNA containing AFB₁-N⁷-guanine or AFB₁-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 AFB₁-N⁷-guanine and AFB₁-formamidopyrimidine adducts 5- and 30-fold more effectively than did mouse lung, and 6- and 4-fold more effectively than did liver extracts from Sprague-Dawley rats. The susceptibility of mouse lung and rat liver to AFB₁-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 AFB₁ 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 AFB₁-N⁷-guanine damage was 3.5-fold higher in liver of AFB₁-treated mice relative to control. This is the first study to show that in vivo treatment with AFB₁ 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 AFB₁, and selective induction of repair in liver contribute to the susceptibility of mice to AFB₁-induced lung tumorigenesis relative to hepatocarcinogenesis.

Key Words: Aflatoxin B₁ • DNA repair • hepatocarcinogenesis • pulmonary carcinogenesis • susceptibility

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