Variations of DNA-(cytosine-5-)-methyltransferase activities after administration of N-hydroxy-N-aminofluorene to Sprague-Dawley rats.
DNA methylation in eukaryotic cells is a post-replicative process involving the transfer of methyl groups from S-adenosyl-L-methionine to the 5 position of cytosine residues through the action of DNA (cytosine-5-)-methyltransferase (DNA-methylase). There are two types of methylation within the cell: a maintenance methylation and a de novo methylation. Its major function is the maintenance methylation of hemimethylated sites after replication in order to preserve the pattern from one generation to the next. Nevertheless DNA-methylase is also able to transfer methyl groups to unmethylated sites in various substrates in a de novo reaction. Male Sprague-Dawley rats have a low specific activity of liver maintenance DNA-methylase and are sensitive to the toxic and carcinogenic effects of N-hydroxy-N-acetylaminofluorene (N-OH-AAF). Female Sprague-Dawley rats, on the contrary, have a 4-5 times higher maintenance DNA-methylase activity and are 6-7 times less sensitive to this carcinogenic effect. Their de novo DNA-methylase activity is the same. When female Sprague-Dawley rats are treated with N-OH-AAF their total DNA-methylase activity diminishes. On the contrary, the maintenance DNA-methylase activity of male Sprague-Dawley rats increases, whereas the de novo activity remains constant. In the spleen, which is not a target organ, the total DNA-methylase activity decreases after injection of N-OH-AAF. These variations of DNA-methylase activity are due to a variation of extractable nuclear DNA-methylase. When Swiss mice, which are not sensitive to the carcinogenic effect, are treated with N-OH-AAF, their total DNA-methylase activity decreases. A decrease of DNA-methylase activity in response to this carcinogen seems to be correlated to the resistance of the animals in developing a hepatocarcinoma.
Pfohl-Leszkowicz
A
A
Institut de Biologie Moléculaire et Cellulaire du CNRS, Université Louis Pasteur, Strasbourg, France.
Pfeifer
G P
GP
Dirheimer
G
G
D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D004198:Disease Susceptibility; D005260:Female; D005449:Fluorenes / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013154:Spleen / Q000187:drug effects
D005449:Fluorenes; C001368:N-hydroxy-2-aminofluorene; D004248:DNA (Cytosine-5-)-Methyltransferases