title: Delay of DNA-adduct repair and severe toxicity in xeroderma pigmentosum group A gene (XPA) deficient mice treated with 2-amino-1-methyl-6-phenyl-imidazo [4,5-b] pyridine (PhIP).
abstract: Group-A xeroderma pigmentosum (XPA) gene-deficient mice are defective in nucleotide-excision repair and highly susceptible to ultraviolet-B-, and 9,10-dimethyl-1,2-benz[a]anthracene (DMBA)-induced skin carcinogenesis. In this study, changes of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP)-DNA adduct formations in the liver, colon and lung, as assessed by the 32P-postlabeling method and immunohistochemical analysis, and carcinogenic and/or toxic susceptibility of both sexes of XPA-deficient mice (XPA-/-) to PhIP, which is a carcinogenic heterocyclic amine, was examined. Levels of PhIP-DNA adduct formations in the liver, colon and lung, were almost twice as high in XPA-/- as in wild type mice (XPA+/+) mice, 7 days after a single i.g. administration of PhIP, and their delay in recovery was observed in XPA-/- mice. For the long-term experiment, XPA-/- and XPA+/+ type mice were treated with 80 ppm PhIP in the diet for the first 4 weeks followed by 40 ppm after a 2-week recovery period (long-term experiment I), or 40 ppm PhIP throughout the experiment (long-term experiment II). Severe toxicity, as evidenced by body weight retardation and poor survival, was observed in the PhIP treated XPA-/- mice of both sexes, but not in the XPA+/+. At week 40 the experiments were terminated and histopathological examinations were performed after complete autopsy. Only lymphomas/leukemias were observed as neoplastic lesions, but no significant differences were observed between the groups. As non-neoplastic lesions, degenerating changes, for example in the pancreatic acinar cells, were observed with XPA-/- mice tending to be more sensitive than XPA+/+ mice. The present study demonstrated that PhIP-DNA adduct formations in the liver, colon and lung of XPA-/- mice were demonstrated and their recovery rate was more delayed than XPA+/+ mice, and furthermore, more severe toxicity to PhIP in XPA-deficient mice was observed, but they were not susceptible to PhIP carcinogenicity under the conditions of the experiment.
authors.affiliation: 1st Department of Pathology, Nagoya City University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Imaida
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Totsuka
authors.forename: K
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Ito
authors.forename: T
authors.initials: T
authors.lastname: Shirai
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005838:Genotype; D007093:Imidazoles / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity*; D013047:Specific Pathogen-Free Organisms; D051760:Xeroderma Pigmentosum Group A Protein
chemical_list: D018736:DNA Adducts; D004268:DNA-Binding Proteins; D007093:Imidazoles; D009153:Mutagens; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine