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 ofS-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 (≈10 μmol/L), MAT activity was decreased at 5 mmol/L but increased at 20 μmol/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.