Tygstrup N, Jensen S A, Krog B, Dalhoff K
Department of Medicine A, Rigshospitalet, Copenhagen, Denmark,
J Hepatol. 1996 Aug;25(2):183-90. doi: 10.1016/s0168-8278(96)80072-9.
In order to study the short-term effect of moderate and severe reduction of liver function by acetaminophen poisoning of different severity on gene expression for liver-specific functions, rats were given 3.75 and 7.5 g per kg body weight acetaminophen intragastrically. The lower dose is associated with low mortality; after the higher dose, most rats die at between 12 and 24 h.
In the morning, 1 1/2, 3, 6, 9, and 12 h after the injection, the rats were killed and RNA was extracted from liver tissue. By slot-blot hybridization mRNA steady-state levels were determined for enzymes involved in metabolic liver functions, i.e. ureagenesis, gluconeogenesis, and drug metabolism, for acute phase proteins, "house-keeping" proteins, and for proteins related to liver regeneration. Results were expressed as per cent of the level in similarly fasted, untreated rats of the same stock
After the smaller dose of acetaminophen, most of the examined mRNA levels were increasing during the experimental period, being two- to four-fold elevated in relation to control after 6 to 12 h. Rats receiving the lethal dose either showed no or a later and smaller increase, and in several cases a fall towards the end of the experiment. The greatest differences were seen for mRNA of arginase, beta-fibrinogen, alpha 1-acid glycoprotein, alpha-tubulin, histone 3, TGF beta, and cyclin d, i.e. proteins associated with acute phase response and liver cell replication and maintenance.
It is concluded that reversible intoxication with acetaminophen induces an adaptive modulation of mRNA expression of liver functions and regeneration which is lacking after severe intoxication. This adaptation, with emphasis on acute phase response and regeneration, may be crucial for recovery after acetaminophen intoxication. If this also applies to the intoxication in man, estimates of the corresponding variables may be clues to the prognosis of acetaminophen-induced fulminant hepatic failure.
为研究不同严重程度的对乙酰氨基酚中毒导致的肝功能中、重度降低对肝脏特异性功能基因表达的短期影响，给大鼠按每千克体重3.75克和7.5克的剂量灌胃给予对乙酰氨基酚。较低剂量与低死亡率相关；给予较高剂量后，大多数大鼠在12至24小时之间死亡。
在注射后的上午1.5、3、6、9和12小时，处死大鼠并从肝脏组织中提取RNA。通过狭缝印迹杂交法测定参与肝脏代谢功能（即尿素生成、糖异生和药物代谢）的酶、急性期蛋白、“管家”蛋白以及与肝脏再生相关蛋白的mRNA稳态水平。结果以相同品系、同样禁食、未处理大鼠的水平的百分比表示。
给予较小剂量的对乙酰氨基酚后，在实验期间大多数检测的mRNA水平升高，在6至12小时后相对于对照组升高了两到四倍。接受致死剂量的大鼠要么没有升高，要么升高出现得较晚且幅度较小，并且在某些情况下在实验末期出现下降。在精氨酸酶、β-纤维蛋白原、α1-酸性糖蛋白、α-微管蛋白、组蛋白3、转化生长因子β和细胞周期蛋白d的mRNA中观察到最大差异，即与急性期反应以及肝细胞复制和维持相关的蛋白。
得出的结论是，对乙酰氨基酚的可逆性中毒诱导了肝功能和再生的mRNA表达的适应性调节，而严重中毒后则缺乏这种调节。这种以急性期反应和再生为重点的适应性调节可能对对乙酰氨基酚中毒后的恢复至关重要。如果这也适用于人类中毒情况，对相应变量的评估可能是对乙酰氨基酚诱导的暴发性肝衰竭预后的线索。
