SPECIFIC LOSS OF THE HIGH-MOLECULAR-WEIGHT FORM OF S-ADENOSYL-L-METHIONINE SYNTHETASE IN HUMAN-LIVER CIRRHOSIS
SPECIFIC LOSS OF THE HIGH-MOLECULAR-WEIGHT FORM OF S-ADENOSYL-L-METHIONINE SYNTHETASE IN HUMAN-LIVER CIRRHOSIS
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DOI：
10.1002/hep.1840080610
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发表时间：
1988-11-01
期刊：
影响因子：
13.5
通讯作者：
MATO, JM
中科院分区：
文献类型：
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作者：
CABRERO, C;DUCE, AM;MATO, JM
我们已经测量了S-腺苷-L-甲硫氨酸合成酶的活性，该酶的高分子量和低分子量形式之间的比率，以及来自一组对照组（n = 6）和六个酒精中毒者（五个肝炎后和一个酒精中毒者）的肝活检中S-腺苷-L-甲硫氨酸的浓度。肝硬化组S-腺苷-L-甲硫氨酸合成酶的总活性明显降低（为对照组的37.5%）。这是由于与对照组中观察到的（460.3 pmol/min/mg蛋白质）相比，抗肿瘤药组中高分子量S-腺苷-L-蛋氨酸合成酶的特异性降低（73.9 pmol/min/mg蛋白质）。尽管S-腺苷-L-甲硫氨酸的合成速率降低（在底物的生理浓度下，高分子量形式的酶的活性是低分子量形式的15倍），但该代谢物的浓度在对照组中是相同的（17.3 ± 0.01）。2.6在抗肿瘤药组（17.8 ± 0.5 μ M）和抗肿瘤药组（17.8 ± 0.5 μ M）中，3.1μ M）。为了解释这些发现，假设在人肝脏中，S-腺苷-L-甲硫氨酸的浓度低于使用该代谢物的各种酶的Km值，（约50至100 μ M），S-腺苷-L-甲硫氨酸合成的减少通过该分子利用率的降低而得到补偿，而不影响S-腺苷-L-甲硫氨酸的肝内浓度。蛋氨酸。通过用半乳糖胺处理降低大鼠肝脏中高分子量S-腺苷-L-甲硫氨酸合成酶的活性来测试这一假设。在大鼠肝脏中，S-腺苷-L-甲硫氨酸的浓度约为100 μ M。半乳糖胺处理将高分子量S-腺苷-L-甲硫氨酸合成酶从对照组（n = 9）的66.5 pmol/min/mg蛋白质降低至31.4 pmol/min/mg蛋白质（n = 8）。这种高分子量S-腺苷-L-甲硫氨酸合成酶活性的降低伴随着S-腺苷-L-甲硫氨酸浓度从111.3 ±-的降低。5.7对照组中为56.9 μ M ± 0.05 μ M。3.2在用半乳糖胺处理的动物组中，我们的研究结果支持了这一假设，即在人类肝硬化有一个显着的S-腺苷-L-蛋氨酸的合成和利用率下降。
We have measured the activity of S-adenosyl-L-methionine synthetase, the ratio between the high- and low-molecular-weight forms of this enzyme and the concentration of S-adenosyl-L-methionine in liver biopsies from a group of controls (n = 6) and in six cirrhotics (five posthepatitic and one alcoholic). The total activity of S-adenosyl-L-methionine synthetase was markedly reduced in cirrhosis (37.5% of that found in the control group). This was due to a specific reduction in the high-molecular-weight S-adenosyl-L-methionien synthetase in the group of cirrhotics (73.9 pmoles per min per mg protein) when compared with that observed in controls (460.3 pmoles per min per mg protein). Despite this reduction in the rate of synthesis of S-adenosyl-L-methionine (the high-molecular-weight form of the enzyme is 15 times more active than the low-molecular-weight form at physiological concentration of substrates), the concentration of this metabolite was the same in the control group (17.3 .+-. 2.6 .mu.M) and in the group of cirrhotics (17.8 .+-. 3.1 .mu.M). To explain these findings, it is postulated that in human liver, where the concentration of S-adenosyl-L-methionine is lower than the Km values of a variety of enzymes that use this metabolite (around 50 to 100 .mu.M), a reduction in the synthesis of S-adenosyl-L-methionine is compensated by a reduction in the rate of utilization of this molecule wihtout affecting the intrahepatic concentration of S-adenosyl-L-methionine. This postulate was tested by decreasing the activity of the high-molecular-weight S-adenosyl-L-methionine synthetase in rat liver by treatment with galactosamine. In the rat liver, the concentration of S-adenosyl-L-methionine is about 100 .mu.M. Galactosamine treatment reduced the high-molecular-weight S-adenosyl-L-methionine synthetase from 66.5 pmoles per min per mg protein in the control group (n = 9) to 31.4 pmoles per min per mg protein (n = 8). This reduction of the activity of the high-molecular weight S-adenosyl-L-methionine synthetase was accompanied by a reduction of the concentration of S-adenosyl-L-methionine from 111.3 .+-. 5.7 .mu.M in the control group to 56.9 .+-. 3.2 .mu.M in the group of animals treated with galactosamine. Our results support the hypothesis that in human cirrhotic liver there is a marked reduction in the rate of synthesis and utilization of S-adenosyl-L-methionine.