Protection of conjugated linoleic acids against 2-amino-3-methylimidazo[4,5-f]quinoline-induced colon carcinogenesis in the F344 rat: a study of inhibitory mechanisms
Grilled ground beef contains a number of heterocyclic amine carcinogens, such as 2-amino-3-methylimidazo[4,5-/Iquinoline (IQ), as well as anticarcinogenic conjugated linoleic acids (CLA). In the present study, CLA was administered to male F344 rats by gavage on alternating days in weeks 1–4, while IQ was given by gavage every other day in weeks 3 and 4 (100 mg/kg body wt). Rats were killed 6 h after the final carcinogen dose in order to quantify IQ-DNA adducts or after week 16 in order to score colonic aberrant crypt foci (ACF). In the ACF study, CLA had no effect on the size of the foci, but inhibited significantly (P 7) for the major adduct were 9.13 ± 2.6 in controls versus 5.42 ± 1.8 in CLA-treated animals (P < 0.05). Mechanism studies indicated that CLA and other fatty acids interact with certain heterocyclic amines in a manner consistent with substrate—ligand binding. However, no such interaction occurred with IQ, and CLA failed to inhibit significantly the mutagenicity ofN-hydroxy-IQ in the Salmonella assay, Liver microsomes from CLA-treated rats exhibited lower activities for dealkylation of 7-ethoxyresorufin and methoxyresorufin and activated IQ to DNA binding species less effectively than microsomes from control animals. Direct addition of CLA to the in vitro incubation inhibited IQ-DNA binding and was associated with increased recovery of unmetabolized parent compound. In the Salmonella assay, CLA inhibited the muta-genic activity of IQ in the presence of S9 or ram seminal vesicle microsomes. Collectively, these results support a mechanism involving inhibition of carcinogen activation by CLA, as opposed to direct interaction with the procarcin-ogen, scavenging of electrophiles or selective induction of phase I detoxification pathways.