Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B₁ and its dependence on p53 genotype.

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.