Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B1 and its dependence on p53 genotype.
Toxicol Appl Pharmacol
; 275(2): 96-103, 2014 Mar 01.
Article
en En
| MEDLINE
| ID: mdl-24380836
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Regulación hacia Arriba
/
Proteína p53 Supresora de Tumor
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Aflatoxina B1
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Reparación del ADN
Límite:
Animals
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Canadá