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)

Citation
K. Imaida et al., 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), CANCER LETT, 150(1), 2000, pp. 63-69
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
CANCER LETTERS
ISSN journal
0304-3835 → ACNP
Volume
150
Issue
1
Year of publication
2000
Pages
63 - 69
Database
ISI
SICI code
0304-3835(20000313)150:1<63:DODRAS>2.0.ZU;2-G
Abstract
Group-A xeroderma pigmentosum (XPA) gene-deficient mice are defective in nu cleotide-excision repair and highly susceptible to ultraviolet-B-, and 9,10 -dimethyl-1,2-benz[a]anthracene (DMBA)-induced skin carcinogenesis [1]. In this study, changes of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (Ph IP)-DNA adduct formations in the liver, colon and lung, as assessed by the P-32-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 twi ce 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 observ ed in XPA(-/-) mice. For the longterm experiment, XPA(-/-) and XPA(+/+) typ e mice were treated with 80 ppm PhIP in the diet for the first 4 weeks foll owed 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 tox icity; as evidenced by body weight retardation and poor survival, was obser ved in the PhIP treated XPA(-/-). mice of both sexes, but not in the XPA(+/ +). At week 40 the experiments were terminated and histopathological examin ations were performed after complete autopsy. Only lymphomas/leukemias were observed as neoplastic lesions, but no significant differences were observ ed between the groups. As non-neoplastic :lesions, degenerating changes, fo r example in the pancreatic acinar cells, were observed with XPA(-/-) mice tending to be more sensitive than XPA(+/+) mice. The present study demonstr ated 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 un der the conditions of the experiment. (C) 2000 Elsevier Science Ireland Ltd . All rights reserved.