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
C. Liew et al., 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, Carcinogenesis, 16(12), 1995, pp. 3037-3043
Grilled ground beef contains a number of heterocyclic amine carcinogen
s, such as 2-amino-3-methylimidazo[4,5f]quinoline (IQ), as well as ant
icarcinogenic conjugated linoleic acids (CLA), In the present study, C
LA 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 an
d 4 (100 mg/kg body wt), Rats were killed 6 h after the final carcinog
en dose in order to quantify IQ-DNA adducts or after week 16 in order
to CLA had no effect on the size of the foci, but inhibited significan
tly (P < 0.05) the number of ACF/colon, from 4.3 +/- 2.4 in controls t
o 1.1 +/- 1.3 in CLA-treated rats (mean +/- SD, n = 10). Rats given CL
A also had significantly lower IQ-DNA adducts in the colon as determin
ed by P-32-postlabeling analysis; relative adduct labeling levels (RAL
x 10(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 indica
ted 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 signif
icantly the mutagenicity of N-hydroxy-IQ in the Salmonella assay, Live
r microsomes from CLA-treated rats exhibited lower activities for deal
kylation of 7-ethoxyresorufin and methoxyresorufin and activated IQ to
DNA binding species less effectively than microsomes from control ani
mals, Direct addition of CLA to the in vitro incubation inhibited IQ-D
NA binding and was associated with increased recovery of unmetabolized
parent compound, In the Salmonella assay, CLA inhibited the mutagenic
activity of IQ in the presence of so or ram seminal vesicle microsome
s, Collectively, these results support a mechanism involving inhibitio
n of carcinogen activation by CLA, as opposed to direct interaction wi
th the procarcinogen, scavenging of electrophiles or selective inducti
on of phase I detoxification pathways.