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Mucosa-preferential DNA Adduct Formation by 2-Amino-3-methylimidazo-[4,5-f]quinoline in the Rat Colonic Wall¹

The Second Department of Surgery [A. K., A. U., K. H., M. T., Y. M.] and Department of Bacteriology [T. K., Y. O.], School of Medicine, The University of Tokushima, Kuramoto-cho, Tokushima 770, Japan

The mechanism of mucosa-specific formation of DNA adducts, which was found recently in human intestines, was studied in male F344 rats treated with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). There are three conceivable pathways for p.o. administered IQ to reach the target colonic mucosal cells: pathway 1, through the digestive canal which exposes from the lumenal direction; pathway 2, following enterohepatic circulation re-expose from the lumenal direction; and pathway 3, exposure via blood circulation. To investigate these possible pathways, the following surgical procedures were performed: (a) portal catheterization for IQ administration to eliminate pathway 1 and (b) choledochal catheterization for bile drainage to eliminate pathway 2. When both procedures are combined, only pathway 3 is active. Four types of IQ-DNA adducts were commonly observed in the colons of all experimental groups, with no qualitative difference between the mucosal and muscular layers. When IQ-HCl was administered by p.o. gavage at a dose of 100 µmol/kg body weight, approximately 70% of the IQ-DNA adducts in the colonic mucosa (13.1 ± 4.3 adducts/10⁷ nucleotides) was induced through pathway 1. Pathway 3 induced the remaining 30% of mucosal adducts, producing equal adduct levels in both layers. Pathway 2 did not work for adduct formation. The DNA adduct formation was unaffected in the presence of intestinal flora, indicating that detoxified IQ does not reactivate by floral enzymes. In conclusion, mucosa-specific DNA adduct formation in the colon is caused most likely by the absorption of carcinogens through the lumen.

¹ This work was supported by Grants-in-Aids from the Ministry of Education, Science, and Culture of Japan.

² To whom requests for reprints should be addressed.

Received 1/ 3/95. Accepted 5/ 1/95.

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