Effect of hypoxia on hepatic DNA methylation and tRNA methyltransferase in rat: similarities to effects of methyl-deficient diets.
Young rats were maintained in a 10% oxygen atmosphere for 2, 6, and 10 days and administered normal rat chow and water ad libitum. Thereafter, their hepatic S-adenosyl-L-methionine (AdoMet) and activity and mRNA levels of AdoMet synthetase were assayed. AdoMet levels decreased by 45% after 10 days; hepatic AdoMet synthetase also declined by approximately 40%. In rats with low hepatic AdoMet, the mRNA level of AdoMet synthetase also declined by up to 80%. No significant change in AdoMet or AdoMet synthetase was noted in pair-fed normoxic rats. DNA hypomethylation was determined in terms of incorporation of [3H]methyl of AdoMet incorporated at unmethylated sites in DNA in reactions mediated by methylases HpaII and SssI. As compared to the normal hepatic DNA, [3H]methyl group incorporation in the 10-day hypoxic DNA was almost double in the HpaII-mediated reaction and approximately 10-fold in the SssI-mediated reaction. Hepatic tRNA methyltransferase activity doubled after 10 days of hypoxia. However, hypoxic rats showed no detectable mRNA transcripts for c-myc and c-fos oncogenes on Northern blot analysis. These observations show that because of subnormal activity of AdoMet synthetase, hypoxic liver is depleted of AdoMet, even when the animals are administered a complete diet. However, unlike rats on chronic lipotrope-deficient diets, hypoxic rats on a complete diet show no aberrant expression of oncogenes.
Chawla
R K
RK
Department of Medicine, Emory University School of Medicine and Research Service, Decatur, Georgia 30033, USA.
Watson
W H
WH
Jones
D P
DP
D000818:Animals; D015152:Blotting, Northern; D004247:DNA / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D012359:tRNA Methyltransferases / Q000187:drug effects / Q000378:metabolism*
D012436:S-Adenosylmethionine; D004247:DNA; D012435:S-Adenosylhomocysteine; D012359:tRNA Methyltransferases; D008716:Methionine Adenosyltransferase