Moore D J, Batts K P, Zalkow L L, Fortune G T, Powis G
Department of Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Toxicol Appl Pharmacol. 1989 Nov;101(2):271-84. doi: 10.1016/0041-008x(89)90276-7.
Indicine N-oxide (INO) is a pyrrolizidine alkaloid (PA) with antitumor activity in animals and humans. Prior studies showed that despite the known hepatic toxicity of the PAs, INO did not produce hepatic toxicity in animals but caused unpredictable lethal hepatic toxicity in humans. In this study we have attempted to find a model system for predicting the hepatotoxic potential of antitumor PAs. Primary cultures of rat hepatocytes showed toxicity only with the most hepatotoxic PAs such as lasiocarpine, but did not detect toxicity with other PAs. Subchronic intraperitoneal administration of PAs to weanling rats and adult mice produced, in surviving animals, hepatic megalocytosis and centrilobular necrosis with heliotrine (H) and 9-O-(R(-)-2-(4'-chlorophenyl)-2-hydroxybutyryl)retronecine N-oxide (RC1NO) but only megalocytosis with INO. Thus, despite previous reports, weanling rats offered no advantage over adult mice for detecting significant hepatic toxicity with PAs. Phenobarbital pretreatment of the mice did not increase the hepatic toxicity of any of the PAs. Subchronic oral administration of PAs to adult mice produced hepatic megalocytosis and centrilobular necrosis in surviving animals with H and RC1NO and megalocytosis with INO. Animals that died acutely following oral administration of INO showed hepatic centrilobular necrosis. Administration of several courses of INO intravenously to dogs produced histological evidence of centrilobular hemorrhagic necrosis. It is concluded that there is no single animal model that will predict hepatic toxicity of the type seen in humans with the antitumor PAs. A combination of studies using adult mice and dogs and lethal doses of the PAs offers the best way of detecting potential hepatic toxicity.
牛磺胆酸N-氧化物（INO）是一种吡咯里西啶生物碱（PA），在动物和人类中具有抗肿瘤活性。先前的研究表明，尽管已知PA具有肝毒性，但INO在动物中不会产生肝毒性，却会在人类中导致不可预测的致命肝毒性。在本研究中，我们试图找到一种模型系统来预测抗肿瘤PA的肝毒性潜力。大鼠肝细胞原代培养仅在最具肝毒性的PA（如倒千里光碱）作用下显示出毒性，但在其他PA作用下未检测到毒性。对断奶大鼠和成年小鼠进行亚慢性腹腔注射PA，在存活的动物中，天芥菜碱（H）和9-O-（R（-）-2-（4'-氯苯基）-2-羟基丁酰）倒千里光裂碱N-氧化物（RC1NO）会导致肝巨细胞症和小叶中心坏死，而INO仅导致肝巨细胞症。因此，尽管有先前的报道，但在检测PA的显著肝毒性方面，断奶大鼠并不比成年小鼠有优势。对小鼠进行苯巴比妥预处理并没有增加任何一种PA的肝毒性。对成年小鼠进行亚慢性口服PA，在存活的动物中，H和RC1NO会导致肝巨细胞症和小叶中心坏死，INO会导致肝巨细胞症。口服INO后急性死亡的动物表现出肝小叶中心坏死。对犬静脉注射几个疗程的INO会产生小叶中心出血性坏死的组织学证据。得出的结论是，没有单一的动物模型能够预测人类中所见的抗肿瘤PA类型的肝毒性。使用成年小鼠和犬以及PA致死剂量的联合研究提供了检测潜在肝毒性的最佳方法。
