title: Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B₁ and its dependence on p53 genotype.
abstract: Aflatoxin B₁(AFB₁) is biotransformed in vivo into an epoxide metabolite that forms DNA adducts that may induce cancer if not repaired. p53 is a tumor suppressor gene implicated in the regulation of global nucleotide excision repair (NER). Male heterozygous p53 knockout (B6.129-Trp53(tm1Brd)N5, Taconic) and wild-type mice were exposed to 0, 0.2 or 1.0 ppm AFB₁ for 26 weeks. NER activity was assessed with an in vitro assay, using AFB₁-epoxide adducted plasmid DNA as a substrate. For wild-type mice, repair of AFB₁-N7-Gua adducts was 124% and 96% greater in lung extracts from mice exposed to 0.2 ppm and 1.0 ppm AFB₁respectively, and 224% greater in liver extracts from mice exposed to 0.2 ppm AFB₁( p<0.05). In heterozygous p53 knockout mice, repair of AFB₁-N7-Gua was only 45% greater in lung extracts from mice exposed to 0.2 ppm AFB₁ (p<0.05), and no effect was observed in lung extracts from mice treated with 1.0 ppm AFB₁or in liver extracts from mice treated with either AFB₁concentration. p53 genotype did not affect basal levels of repair. AFB₁exposure did not alter repair of AFB₁-derived formamidopyrimidine adducts in lung or liver extracts of either mouse genotype nor did it affect XPA or XPB protein levels. In summary, chronic exposure to AFB₁increased NER activity in wild-type mice, and this response was diminished in heterozygous p53 knockout mice, indicating that loss of one allele of p53 limits the ability of NER to be up-regulated in response to DNA damage.
authors.affiliation: Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Mulder
authors.affiliation: Toxicology Research Division, 2202D, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Genevieve S
authors.initials: GS
authors.lastname: Bondy
authors.affiliation: Toxicology Research Division, 2202D, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada.
authors.forename: Rekha
authors.initials: R
authors.lastname: Mehta
authors.affiliation: Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University Kingston, Ontario K7L 3N6, Canada. Electronic address: masseyt@queensu.ca.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D000483:Alleles; D000818:Animals; D001711:Biotransformation; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics*; D005838:Genotype; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D016604:Aflatoxin B1
keywords: Aflatoxin B(1); Chronic; Nucleotide excision repair; p53 genotype