Model systems for detecting the hepatic toxicity of pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides.
Model systems for detecting the hepatic toxicity of pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides.
复制标题
用于检测吡咯里西啶生物碱和吡咯里西啶生物碱 N-氧化物的肝毒性的模型系统。
DOI：
10.1016/0041-008x(89)90276-7
复制
发表时间：
1989
影响因子：
3.8
通讯作者：
Powis,G
中科院分区：
文献类型：
--
作者：
Moore,DJ;Batts,KP;Zalkow,LL;FortuneJr,GT;Powis,G
N-氧化吲哚辛（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，但在人类中会引起不可预测的致死性肝毒性。在这项研究中，我们试图找到一个模型系统，用于预测抗肿瘤PA的肝毒性潜力。大鼠肝细胞的原代培养物显示出毒性，只有最肝毒性的PA，如毛果芸香碱，但没有检测到毒性与其他PA。对断奶大鼠和成年小鼠亚慢性腹膜内给予PA，在存活动物中，天芥菜碱（H）和9-O-（R（−）-2-（4′-氯苯基）-2-羟基丁酰基）反曲酶N-氧化物（RC 1 NO）导致肝巨红细胞增多和小叶中心坏死，但INO仅导致巨红细胞增多。因此，尽管先前有报告，但断奶大鼠在检测PA的显著肝毒性方面并不优于成年小鼠。小鼠的苯巴比妥预处理未增加任何PA的肝毒性。亚慢性口服给药的PA成年小鼠产生肝巨细胞增生和小叶中心坏死存活的动物与H和RC 1 NO和巨细胞增生与INO。经口给予INO后急性死亡的动物显示肝小叶中心坏死。犬静脉注射几个疗程的INO后，出现小叶中心出血性坏死的组织学证据。可以得出结论，没有单一动物模型可以预测抗肿瘤PA在人体中观察到的肝毒性类型。使用成年小鼠和犬以及致死剂量的PA的研究组合提供了检测潜在肝毒性的最佳方法。
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.