Reversal by 5-azacytidine of the S-adenosyl-L-methionine-induced inhibition of the development of putative preneoplastic foci in rat liver carcinogenesis.
The development of gamma-glutamyltranspeptidase (GGT)-positive foci, in Wistar rats, initiated with diethylnitrosamine and subjected to selection according to 'resistant hepatocyte' protocol, was coupled, 7 weeks after initiation, with liver DNA hypomethylation and with a fall in S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio, and in 5-methylthio-adenosine (MTA) content. A 15-day treatment with SAM, started 1 week after selection, caused a dose-dependent decrease in the development of GGT-positive foci, recovery of liver SAM/SAH ratio and MTA level, and liver DNA methylation. A 12-day treatment with 20 mumol/kg per day of 5-azacytidine (AzaC), starting 1 week after selection, enhanced growth of GGT-positive foci, caused strong DNA hypomethylation, and partially counteracted the inhibition of GGT-positive foci growth, without affecting recovery of SAM/SAH ratio and MTA level, induced by SAM. These results suggest a role of DNA methylation in the antipromoting effect of SAM.
Pascale
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R
Institute of General Pathology, University of Sassari, Italy.
Simile
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Ruggiu
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Seddaiu
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Satta
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Sequenza
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Daino
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Vannini
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Lai
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D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D003839:Deoxyadenosines; D004052:Diethylnitrosamine; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism / Q000494:pharmacology*; D013872:Thionucleosides / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D003839:Deoxyadenosines; D013872:Thionucleosides; D004052:Diethylnitrosamine; C008500:5'-methylthioadenosine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D005723:gamma-Glutamyltransferase; D000241:Adenosine; D001374:Azacitidine