Differential effect of thioacetamide on hepatic methionine adenosyltransferase expression in the rat.
Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM), the principal methyl donor. Mature liver expresses mainly MAT1A. We showed a switch from MAT1A to MAT2A gene expression in human liver cancer cells that may offer a growth advantage. To gain a better understanding of the chronology and significance of the change in MAT expression, we examined changes in hepatic MAT expression after acute treatment of rats with a hepatocarcinogen, thioacetamide (TAA). TAA treatment for 3 weeks did not change the MAT1A mRNA level but reduced the liver-specific MAT protein level to below 30% of control. TAA also acutely reduced the activity of liver-specific MAT when added to normal liver homogenates. In contrast, both the mRNA and protein levels of non-liver-specific MAT were induced. Because liver-specific MAT exhibits a much higher Km for methionine (mmol/L) than non-liver-specific MAT ( approximately 10 micromol/L), MAT activity was decreased at 5 mmol/L but increased at 20 micromol/L methionine concentration. The SAM level, SAM-to-S-adenosylhomocysteine (SAH) ratio, and DNA methylation all fell during treatment. In summary, TAA treatment induced differential changes in hepatic MAT expression. The reduction in liver-specific MAT protein level represents a novel mechanism of inactivation of liver-specific MAT. This along with induction in MAT2A contributed to a fall in the SAM-to-SAH ratio. The resulting DNA hypomethylation may be important in the process of hepatocarcinogenesis.
Huang
Z Z
ZZ
Division of Gastroenterology and Liver Diseases, USC Liver Disease Research Center, USC School of Medicine, Los Angeles, CA 90033, USA.
Mato
J M
JM
Kanel
G
G
Lu
S C
SC
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013853:Thioacetamide / Q000494:pharmacology*
D002273:Carcinogens; D007527:Isoenzymes; D013853:Thioacetamide; D012436:S-Adenosylmethionine; D004247:DNA; D012435:S-Adenosylhomocysteine; D008716:Methionine Adenosyltransferase