[Phenobarbital-induced hypermethylation of the p53 promoter region in the liver of Wistar rats].
Non-genotoxic carcinogens (NGCs)-induced changes of DNA methylation has been proposed as a mechanism of their toxicity, including carcinogenic action. The effect of phenobarbital (PB), a rodent liver carcinogen on the methylation level of the p53 promoter region in rat liver was studied. Changes in the methylation status of the p53 gene were correlated with changes in DNA synthesis, DNA methyltransferase (DNMTs) activity and liver weight. Male Wistar rats received PB in one, three or fourteen daily oral doses of 92.8 mg/kg b.w. x day(-1). We have demonstrated that PB increased the methylation of the p53 gene. Cytosine hypermethylation in the analyzed CpG sites of the p53 gene promoter occurred during the whole period of study. However, an increase in DNA synthesis was only observed after 1 and 3 days of treatment with PB and it preceded liver growth. Treatment of rats with PB for 1 and 3 days also produced an increase in nuclear DNMTs activity. After prolonged administration (14 days), no changes in DNMTs activity nor DNA synthesis were observed. It is proposed that PB-induced de novo methylation of the p53 gene was not associated with DNMTs activity.
Kostka
Grazyna
G
Zakład Toksykologii Srodowiskowej, Narodowy Instytut Zdrowia Publicznego - Państwowy Zakład Higieny, 00-791 Warszawa, ul. Chocimska 24. gkostka@pzh.gov.pl
Urbanek-Olejnik
Katarzyna
K
Wiadrowska
Bozena
B
Bańkowski
Robert
R
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D018899:CpG Islands / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D019175:DNA Methylation; D004261:DNA Replication / Q000187:drug effects; D019942:Genes, p16 / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010634:Phenobarbital