Putnam C W, Buckley A R, Warneke J A, Karrer F M, Rhenman B, Steinbronn K
Surgery. 1984 Aug;96(2):214-22.
Hepatic neutral serine proteases (including plasminogen activator) and ornithine decarboxylase (ODC) are induced by the hepatotoxin galactosamine (GALN). We examined the hepatoprotection conferred by epsilon-aminocaproic acid (EACA), a fibrinolytic inhibitor, putrescine (PUTR), the polyamine generated from ornithine by ODC, and alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. GALN, 450 mg/kg, was administered intraperitoneally to Wistar-Lewis rats (group I). Groups II, III, and IV were also given EACA (80 mg/kg), PUTR (0.3 mmol/kg), or DFMO (0.3 mmol/kg), respectively, 1 hour before and 3, 7, and 12 hours after GALN. Rats were killed 2 hours after an intraperitoneal dose of 3H-thymidine was administered, 30 or 45 hours after GALN. EACA and PUTR were effective protectants against necrosis as judged by enzymes and histologic findings. Neither increased thymidine incorporation above the levels seen with GALN only. DFMO offered no protection even though thymidine incorporation at 45 hours was increased. Both EACA and PUTR, which have similar chemical structures, possessed significant antiprotease activity in vitro, suggesting that they act by inhibiting toxin-induced neutral serine protease activity and not by accelerating regeneration.
肝中性丝氨酸蛋白酶（包括纤溶酶原激活剂）和鸟氨酸脱羧酶（ODC）可被肝毒素半乳糖胺（GALN）诱导。我们研究了纤溶抑制剂ε-氨基己酸（EACA）、由ODC将鸟氨酸生成的多胺腐胺（PUTR）以及ODC的不可逆抑制剂α-二氟甲基鸟氨酸（DFMO）所提供的肝保护作用。将450mg/kg的GALN腹腔注射给Wistar-Lewis大鼠（第一组）。第二、三、四组在GALN给药前1小时以及给药后3、7和12小时分别给予EACA（80mg/kg）、PUTR（0.3mmol/kg）或DFMO（0.3mmol/kg）。在腹腔注射3H-胸腺嘧啶核苷后2小时、GALN给药后30或45小时处死大鼠。从酶学和组织学结果判断，EACA和PUTR是有效的抗坏死保护剂。二者均未使胸苷掺入量高于仅使用GALN时的水平。尽管45小时时胸苷掺入量增加，但DFMO未提供保护作用。化学结构相似的EACA和PUTR在体外均具有显著的抗蛋白酶活性，这表明它们的作用机制是抑制毒素诱导的中性丝氨酸蛋白酶活性，而非加速肝细胞再生。
