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]pyri dine (PhIP) were studied in DNA repair deficient XPA(-/-) mice, The nullizy gous XPA-knockout mice, which lack a functional nucleotide excision repair (NER) pathway, were exposed to dietary concentrations ranging from 10 to 20 0 p,p,m, The results show that PhIP is extremely toxic to XPA(-/-) mice, ev en 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 administratio n of 200 and 100 p.p.m., respectively. Intestinal abnormalities like disten ded and overfilled ileum and caecum, together with clear signs of starvatio n, suggests that the small intestines were the primary target tissue for th e severe toxic effects. Mutation analysis in XPA-/- mice carrying a lacZ re porter gene, indicated that the observed toxicity of PhIP might be caused b y genotoxic effects in the small intestine. LacZ mutant frequencies appeare d to be selectively and dose-dependently increased in the intestinal DNA of treated XPA(-/-) mice. Furthermore, DNA repair deficient XPC-/- mice, whic h are still able to repair DNA damage in actively transcribed genes, did no t display any toxicity upon treatment with PhIP (100 p,p,m,), This suggests that transcription coupled repair of DNA damage (PhIP adducts) in active g enes plays a crucial role in preventing the intestinal toxicity of PhIP, Fi nally, 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, signif icantly 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 obs erved.