Modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mutation in the cecum and colon of big blue rats by conjugated linoleic acid and 1,2-dithiole-3-thione.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent mutagen and suspected human carcinogen present in cooked protein-rich food. It preferentially induced colon tumors in male rats and mammary tumors in female rats. In the present study, the in vivo antimutagenic efficacy of two dietary compounds, conjugated linoleic acid (CLA) and 1,2-dithiole-3-thione (DTT), against PhIP was explored using 1acI transgenic Big Blue rats. Five- or six-week-old male Big Blue rats were fed a diet containing CLA (0.5%, wt/wt) or DTT (0.005%, wt/wt) starting one week before exposure to 200 ppm PhIP for 61 days. PhIP treatment induced a approximately 8- to 16-fold increase in the mutation frequency (MF) in the colon. The induced MF was significantly lower in the cecum than in the proximal and distal colon (approximately 52 x 10(-5) vs. 100 x 10(-5), p < 0.008). CLA and DTT significantly reduced the PhIP-induced MF in the distal colon (p < 0.05) by 14% and 24%, respectively. The frequency of -1 frameshift mutations was lower in the distal colon of CLA- or DTT-treated rats. This protective effect was not observed in the cecum or in the proximal colon. In contrast, the PhIP-induced MF in the cecum (specifically, the frequency of -1 frameshifts and GC-->TA transversions) was elevated by 43% after treatment with CLA. In conclusion, CLA and DTT modulate PhIP-induced mutagenesis in a tissue-specific manner, and different modulation pathways are employed by CLA and DTT.
Yang
H
H
Centre for Environmental Health, University of Victoria, Victoria, BC, Canada V8W 3N5.
Stuart
G R
GR
Glickman
B W
BW
de Boer
J G
JG
D000818:Animals; D030801:Animals, Genetically Modified; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D002432:Cecum / Q000187:drug effects*; D003106:Colon / Q000187:drug effects*; D004032:Diet; D004435:Eating / Q000187:drug effects; D029968:Escherichia coli Proteins; D016368:Frameshift Mutation; D007093:Imidazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D056968:Lac Repressors; D019787:Linoleic Acid; D008297:Male; D009153:Mutagens / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D007093:Imidazoles; D056968:Lac Repressors; D009153:Mutagens; D012097:Repressor Proteins; D013871:Thiones; D013876:Thiophenes; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019787:Linoleic Acid; C049325:1,2-dithiol-3-thione