Differential effect of thioacetamide on hepatic methionine adenosyltransferase expression in the rat
Differential effect of thioacetamide on hepatic methionine adenosyltransferase expression in the rat
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DOI：
10.1002/hep.510290525
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发表时间：
1999-05-01
期刊：
影响因子：
13.5
通讯作者：
Lu, SC
中科院分区：
文献类型：
--
作者：
Huang, ZZ;Mato, JM;Lu, SC
肝特异性和非肝特异性甲硫氨酸腺苷转移酶（MAT）分别是两个基因MAT 1A和MAT 2A的产物，它们催化主要甲基供体S-腺苷甲硫氨酸（SAM）的形成。成熟的肝脏主要表达MAT 1A，我们发现在人肝癌细胞中从MAT 1A到MAT 2A基因表达的转换可能提供生长优势。为了更好地了解MAT表达变化的时序和意义，我们研究了用肝癌原硫代乙酰胺（TAA）急性治疗大鼠后肝脏MAT表达的变化。TAA处理3周没有改变MAT 1A mRNA水平，但将肝脏特异性MAT蛋白水平降低至对照的30%以下。TAA也急剧降低活性的肝脏特异性MAT时，加入到正常的肝匀浆。相反，非肝特异性MAT的mRNA和蛋白水平均被诱导。由于肝特异性MAT对蛋氨酸的Km值（mmol/L）比非肝特异性MAT（约10 μ mol/L）高得多，因此MAT活性在5 mmol/L时降低，但在20 μ mol/L蛋氨酸浓度时升高。SAM水平、SAM与S-腺苷高半胱氨酸（SAH）比率和DNA甲基化在处理期间均下降。总之，TAA处理诱导了肝脏MAT表达的差异性变化。肝脏特异性MAT蛋白水平的降低代表了肝脏特异性MAT失活的新机制。这沿着MAT 2A中的诱导导致SAM与SAM比率下降。由此产生的DNA低甲基化在肝癌发生过程中可能是重要的。
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-liverspecific MAT 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 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-SAM ratio. The resulting DNA hypomethylation may be important in the process of hepatocarcinogenesis.