Conjugated linoleic acid inhibits mutagenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the prostate of Big Blue rats.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent mutagen and carcinogen formed at high temperature during the cooking of meat. PhIP induces tumors in the colon and prostate of male rats and in the mammary gland of female rats and has been associated with the etiology of human cancers. We have recently demonstrated that PhIP induces mutations in the prostate in Big Blue transgenic rats. In the current study we have examined the effect of a dietary anti-carcinogen, conjugated linoleic acid (CLA), on PhIP-induced mutagenesis in the prostate. CLA is a mixture of positional and geometric isomers of linoleic acid and has been reported to inhibit various chemical-induced cancers in rodent models. Fifty day old male Big Blue rats were fed a standard diet containing 100 p.p.m. PhIP for 47 days, which induced a mutation frequency of 14.6 x 10(-5) in the prostate, 5.1-fold higher than that of controls. The addition of 1% CLA (w/w) in the diet starting 1 week prior to exposure to PhIP decreased PhIP-induced mutagenesis by 38% (P = 0.03). The predominant class of mutation induced by PhIP is -1 frameshifts involving the loss of G:C base pairs, followed by G:C-->T:A transversions and G:C-->A:T transitions. Addition of CLA to the diet significantly changed the PhIP-induced mutation spectrum; notably, -1 frameshifts and G:C-->A:T transitions were selectively inhibited, suggesting involvement of mismatch repair. This is the first report to show the protective effect of CLA against PhIP-induced mutagenesis in the prostate on both mutation frequency and mutational spectrum. The inhibitory effect of CLA against PhIP-induced mutagenicity suggests a possibility for its application in human chemoprevention studies.
Yang
Haiyan
H
Department of Biology, University of Victoria, Victoria, BC V8W 3N5, Canada.
Holcroft
James
J
Glickman
Barry W
BW
de Boer
Johan G
JG
D000818:Animals; D030801:Animals, Genetically Modified; D020137:Base Pair Mismatch; D002273:Carcinogens; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007093:Imidazoles; D019787:Linoleic Acid / Q000494:pharmacology*; D008297:Male; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D009153:Mutagens; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011467:Prostate / Q000187:drug effects*; D051381:Rats; D013997:Time Factors
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019787:Linoleic Acid; D010100:Oxygen