MUCOSA-PREFERENTIAL DNA ADDUCT FORMATION BY 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE IN THE RAT COLONIC WALL

The mechanism of mucosa-specific formation of DNA adducts, which was f ound recently in human intestines, was studied in male F344 rats treat ed with 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). There are three conceivable pathways for p.o. administered IQ to reach the target colo nic mucosal cells: pathway 1, through the digestive canal which expose s from the lumenal direction; pathway 2, following enterohepatic circu lation re-expose from the lumenal direction; and pathway 3, exposure v ia blood circulation. To investigate these possible pathways, the foll owing surgical procedures were performed: (a) portal catheterization f or IQ administration to eliminate pathway 1 and (b) choledochal cathet erization for bile drainage to eliminate pathway 2. When both procedur es are combined, only pathway 3 Is active. Four types of IQ-DNA adduct s were commonly observed in the colons of all experimental groups, wit h no qualitative difference between the mucosal and muscular layers. W hen IQ-HCl was administered by p.o. gavage at a dose of 100 mu mol/kg body weight, approximately 70% of the IQ-DNA adducts in the colonic mu cosa (13.1 +/- 4.3 adducts/10(7) nucleotides) was induced through path way 1. Pathway 3 induced the remaining 30% of mucosal adducts, produci ng equal adduct levels in both layers. Pathway 2 did not work for addu ct 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 formatio n in the colon is caused most likely by the absorption of carcinogens through the lumen.