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. Matur e 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 ch ange 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 l iver-specific MAT protein level to below 30% of control. TAA also acutely r educed the activity of liver-specific MAT when added to normal liver homoge nates. In contrast, both the mRNA and protein levels of non-liverspecific M AT were induced. Because liver-specific MAT exhibits a much higher K-m for methionine (mmol/L) than non-liver-specific MAT (approximate to 10 mu mol/L ), MAT activity was decreased at 5 mmol/L but increased at 20 mu mol/L meth ionine concentration, The SAM level, SAM-to-S-adenosylhomocysteine (SAH) ra tio, and DNA methylation all fell during treatment. In summary, TAA treatme nt induced differential changes in hepatic MAT expression. The reduction in liver-specific MAT protein level represents a novel mechanism of inactivat ion of liver-specific MAT. This along with induction in MAT2A contributed t o a fall in the SAM-to-SAM ratio. The resulting DNA hypomethylation may be important in the process of hepatocarcinogenesis.