Intestinal toxicity and carcinogenic potential of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in DNA repair deficient XPA-/- mice.
The effects of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were studied in DNA repair deficient XPA(-/-) mice. The nullizygous XPA-knockout mice, which lack a functional nucleotide excision repair (NER) pathway, were exposed to dietary concentrations ranging from 10 to 200 p.p.m. The results show that PhIP is extremely toxic to XPA(-/-) mice, even at doses 10-fold lower than tolerated by wild-type C57BL/6 mice. XPA(-/-) mice rapidly lost weight and died within 2 and 6 weeks upon administration of 200 and 100 p.p.m., respectively. Intestinal abnormalities like distended and overfilled ileum and caecum, together with clear signs of starvation, suggests that the small intestines were the primary target tissue for the severe toxic effects. Mutation analysis in XPA(-/-) mice carrying a lacZ reporter gene, indicated that the observed toxicity of PhIP might be caused by genotoxic effects in the small intestine. LacZ mutant frequencies appeared to be selectively and dose-dependently increased in the intestinal DNA of treated XPA(-/-) mice. Furthermore, DNA repair deficient XPC(-/-) mice, which are still able to repair DNA damage in actively transcribed genes, did not display any toxicity upon treatment with PhIP (100 p.p.m.). This suggests that transcription coupled repair of DNA damage (PhIP adducts) in active genes plays a crucial role in preventing the intestinal toxicity of PhIP. Finally, PhIP appeared to be carcinogenic for XPA(-/-) mice at subtoxic doses. Upon treatment of the mice for 6 months with 10 or 25 p.p.m. PhIP, significantly increased tumour incidences were observed after a total observation period of one year. At 10 p.p.m. only lymphomas were found, whereas at 25 p.p.m. some intestinal tumours (adenomas and adenocarcinomas) were also observed.
Klein
J C
JC
Laboratory of Health Effects Research, National Institute of Public Health and the Environment, PO Box 1, 3720 BA Bilthoven,The Netherlands.
Beems
R B
RB
Zwart
P E
PE
Hamzink
M
M
Zomer
G
G
van Steeg
H
H
van Kreijl
C F
CF
D000230:Adenocarcinoma / Q000139:chemically induced; D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017930:Genes, Reporter; D005838:Genotype; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000633:toxicity*; D007414:Intestinal Neoplasms / Q000139:chemically induced; D007421:Intestine, Small / Q000187:drug effects; D007422:Intestines / Q000187:drug effects*; D007763:Lac Operon; D008223:Lymphoma / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity*; D012737:Sex Factors; D013997:Time Factors; D014158:Transcription, Genetic
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine