Gebhardt R, Burger H J, Heini H, Schreiber K L, Mecke D
Physiologische-chemisches Institut, Universität Tübingen, Federal Republic of Germany.
Hepatology. 1988 Jul-Aug;8(4):822-30. doi: 10.1002/hep.1840080421.
Glutamine synthetase shows a striking heterogeneous distribution in normal rat liver as consistently revealed by immunohistochemistry using a specific antiserum against the rat liver enzyme or a cross-reacting antiserum. The effects of zonal liver injury induced by allylformate or CCl4 on this distribution and on the activity of glutamine synthetase as well as of enzymes with different acinar distribution were investigated. Treatment with allylformate or CCl4 at appropriate concentrations led to severe hepatocyte necrosis in the periportal and perivenous zone, respectively, as revealed by histological examination and by the levels of serum marker enzymes. Exposure to allylformate (50 to 100 microliter per kg) for less than 1 day did not change the distribution and activity of glutamine synthetase but reduced the specific activities of the urea cycle enzymes. In contrast, treatment with CCl4 (1,000 microliter per kg) strongly reduced the activity and the acinar region covered by glutamine synthetase but not, for instance, the activities of the urea cycle enzymes. These results in conjunction with the data obtained for other enzymes indicate that a short exposure to these hepatotoxins affects different enzyme activities in close accord with their preferential acinar localization. During prolonged exposure this initial response was often modified due to adaptation. In the case of glutamine synthetase, however, no adaptive appearance of glutamine synthetase in other parts of the acinus could be detected even if the cell population originally expressing this phenotype was destroyed. This extremely inflexible distribution suggests that glutamine synthetase expression is a matter of cell differentiation rather than of modulation by nutritional and hormonal factors (or their acinar gradients) as found for many other hepatic enzymes.
谷氨酰胺合成酶在正常大鼠肝脏中呈现出显著的异质性分布，使用针对大鼠肝脏该酶的特异性抗血清或交叉反应抗血清进行免疫组织化学检测时，这种分布始终清晰可见。研究了甲酸烯丙酯或四氯化碳诱导的肝小叶损伤对这种分布以及谷氨酰胺合成酶活性，以及对具有不同腺泡分布的酶活性的影响。组织学检查和血清标志物酶水平显示，用适当浓度的甲酸烯丙酯或四氯化碳处理分别导致门静脉周围和肝静脉周围区域的严重肝细胞坏死。暴露于甲酸烯丙酯（每千克50至100微升）少于1天，并未改变谷氨酰胺合成酶的分布和活性，但降低了尿素循环酶的比活性。相比之下，用四氯化碳（每千克1000微升）处理则强烈降低了谷氨酰胺合成酶的活性以及该酶所覆盖的腺泡区域，但例如并未降低尿素循环酶的活性。这些结果与其他酶所获得的数据表明，短期暴露于这些肝毒素会根据其在腺泡中的优先定位，对不同的酶活性产生不同影响。在长期暴露过程中，由于适应性，这种初始反应常常会发生改变。然而，就谷氨酰胺合成酶而言，即使最初表达该表型的细胞群体被破坏，在腺泡的其他部位也未检测到谷氨酰胺合成酶的适应性出现。这种极其固定不变的分布表明，谷氨酰胺合成酶的表达是细胞分化的问题，而不是像许多其他肝酶那样受营养和激素因素（或其腺泡梯度）调节的问题。
