Increased benzodiazepine‐like activity is neither necessary nor sufficient to explain acute hepatic encephalopathy in the thioacetamide‐treated rat-猫眼课题宝

苯二氮卓样活性的增加既不足以解释硫代乙酰胺治疗大鼠的急性肝性脑病

DOI：

发表时间：

1993

期刊：

Hepatology

影响因子：

13.5

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Peter Widler;H. Fisch;P. Schoch;Arthur Zimmermann;T. Schläpfer;J. Reichen

已提出体内产生（内源性）或与食物一起摄入（外源性）的天然苯二氮卓受体激动剂水平升高是导致实验动物和人类受试者肝性脑病的因素之一。然而，肝性脑病对苯二氮卓类拮抗剂的不同反应使人们对这一有吸引力的假设产生怀疑。在雄性Sprague-道利大鼠（n = 17）中通过腹膜内硫代乙酰胺（600 mg/kg/天，持续3天）诱导急性肝衰竭，而14只对照大鼠仅接受溶剂。所有给药大鼠均发生急性肝衰竭（AST：1，898 ± 1，359 IU/L vs.对照组，45 ± 5 IU/L，p < 0.005;胆红素：36 ± 27 μmol/L vs.对照组，1.5 ± 0.5 μmol/L，p < 0.005;中心区坏死）和3级或4级肝性脑病（神经系统评估和活动监测）。然而，采用[3 H]氟马西尼结合竞争试验在全脑匀浆上清液中测量的苯二氮卓类受体配体活性，与对照组相比，17只急性肝衰竭大鼠中仅1只明显增加（52.7 ± 34.1 vs 44.3 ± 18.9 ng地西泮当量/gm; NS）。为了评价报告的苯二氮卓类受体配体活性增加是否可能是由于外源性苯二氮卓类物质的长期滞留所致，对其他急性肝功能衰竭大鼠和对照大鼠进行地西泮给药（灌胃给药5次，每次0.5 mg/kg，间隔12 h）。在最后一次地西泮给药后1至3小时，急性肝功能衰竭动物的苯二氮卓受体配体活性高于对照组（223 ± 65 ng地西泮当量/gm对103 ± 23 ng地西泮当量/gm; p < 0.002）。因此，苯二氮卓受体配体活性的组织水平增加既不必要也不足以解释急性肝衰竭肝性脑病的发病机制。我们得出结论，肝性脑病中苯二氮卓类受体激动剂的组织水平增加可能是由于药物或天然来源的外源性苯二氮卓类化合物的长期驻留。（《肝脏学》1993年;18：1459-1464）

Increased levels of natural benzodiazepine receptor agonists, produced in the body (endogenous) or ingested with food (exogenous) have been proposed as one of the factors causing hepatic encephalopathy in both experimental animals and human subjects. However, the divergent response of hepatic encephalopathy to benzodiazepine antagonists sheds doubt on this attractive hypothesis. Acute liver failure was induced in male Sprague‐Dawley rats (n = 17) with intraperitoneal thioacetamide (600 mg/kg/day for 3 days) while 14 control rats received vehicle only. Acute liver failure developed in all treated rats (AST: 1,898 ± 1,359 IU/L vs. controls, 45 ± 5 IU/L, p < 0.005; bilirubin: 36 ± 27 μmol/L vs. controls, 1.5 ± 0.5 μmol/L, p < 0.005; centrizonal necrosis) and grade 3 or 4 hepatic encephalopathy (neurologic assessment and activity monitoring). However, benzodiazepine receptor ligand activity, measured in the supernatant of whole‐brain homogenates with a [3H]fiumazenil binding competition assay, was clearly increased in only 1 of 17 rats with acute liver failure compared with controls (52.7 ± 34.1 vs. 44.3 ± 18.9 ng diazepam equivalents/gm; NS). To evaluate whether the reported increase in benzodiazepine receptor ligand activity could be due to prolonged residence of exogenous benzodiazepine‐like substances, additional rats with acute liver failure and controls were treated with diazepam (five doses of 0.5 mg/kg at 12‐hr intervals by gavage). Benzodiazepine receptor ligand activity was greater in animals with acute liver failure than in controls (223 ± 65 vs. 103 ± 23 ng diazepam equivalents/gm; p < 0.002) 1 to 3 hr after the last diazepam dose. Increased tissue levels of benzodiazepine receptor ligand activity are therefore neither necessary nor sufficient to explain the pathogenesis of hepatic encephalopathy in acute liver failure. We conclude that increased tissue levels of benzodiazepine receptor agonists in hepatic encephalopathy could be due to prolonged residence of exogenous benzodiazepine‐like compounds of pharmaceutical or natural origin. (HEPATOLOGY 1993;18:1459–1464.)

Purification of a benzodiazepine from bovine brain and detection of benzodiazepine-like immunoreactivity in human brain.