Mutations induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in cecum and proximal and distal colon of lacI transgenic rats.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a food-borne mutagen and carcinogen that induces tumors of the colon and the prostate gland in male rats and of the mammary gland in female rats. In this study we describe the frequency and specificity of PhIP-induced mutations in the cecum, proximal colon and distal colon of male and female lacI transgenic rats. This is the first report of mutational data from discrete regions of the colon. After 61 days of treatment with 200 p.p.m. PhIP mixed into the diet, PhIP-induced mutant frequencies were elevated 7-fold in the cecum and 14- to 21-fold in the colon of male and female rats compared with untreated controls. PhIP-induced mutant frequencies increased significantly (overall trend, P < 10(-4)) along the length of the colon of both males and females, with cecum < proximal colon < distal colon. A total of 754 PhIP mutants (363 male, 391 female) were sequenced to provide the mutational spectra for each of the three tissue sections from males and females. These mutational spectra consisted predominantly of G:C-->T:A and G:C-->C:G transversions and deletions of G:C base pairs. There were no significant differences between the mutational spectra with respect to sex or position in the colon. Therefore, we surmise that following induction of mutations by PhIP in male and female colons, non-mutagenic factors, possibly hormonal, preferentially influence the formation of tumors in the colon of male rats.
Stuart
G R
GR
Centre for Environmental Health and Department of Biology, University of Victoria, PO Box 3020 STN CSC, Victoria, British Columbia, Canada V8W 3N5. stuart@niehs.nih.gov
de Boer
J G
JG
Haesevoets
R
R
Holcroft
J
J
Kangas
J
J
Sojonky
K
K
Thorleifson
E
E
Thornton
A
A
Walsh
D F
DF
Yang
H
H
Glickman
B W
BW
D000818:Animals; D030801:Animals, Genetically Modified; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002432:Cecum / Q000187:drug effects* / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D029968:Escherichia coli Proteins; D005260:Female; D007093:Imidazoles / Q000633:toxicity*; D056968:Lac Repressors; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity; D009154:Mutation / Q000187:drug effects* / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D007093:Imidazoles; D056968:Lac Repressors; D009153:Mutagens; D012097:Repressor Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine