Mattocks A R, Driver H E
Toxicology Unit, Medical Research Council Laboratories, Carshalton, Surrey, U.K.
Chem Biol Interact. 1987;63(1):91-104. doi: 10.1016/0009-2797(87)90107-4.
The effects of anacrotine, a pyrrolizidine alkaloid (PA) which has the structure of senecionine with an additional 6-hydroxy group, have been investigated in weanling male rats. When anacrotine was given i.p. (100 mg/kg), pyrrolic metabolites reached a peak level in the liver during the first 0.5 h, then fell rapidly to a lower level which subsequently declined more slowly. Pyrrolic metabolites accumulated in the lungs during the first hour to a level which then remained relatively steady for at least 4 h. The lung level of pyrrolic metabolites after 2 h was about 39% of the liver level, compared with 16% in rats given senecionine. Anacrotine caused acute centrilobular necrosis and congestion of the liver when 125 mg/kg or more was given i.p., but oral doses (up to 180 mg/kg) caused relatively little liver necrosis. Enlarged hepatocytes developed during ensuing weeks, but these were moderate compared with the bizarre giant cells often associated with pyrrolizidine intoxication. In contrast, anacrotine produced much more severe lung damage than most other pyrrolizidine alkaloids. The lungs were affected by i.p. or oral doses well below those needed to produce acute liver damage. Pulmonary congestion and oedema, extensive necrosis of the pulmonary endothelium, and thickening of alveolar septae, developed within 2 days after dosing. After single i.p. doses of 60 mg/kg or more progressive consolidation of lung tissue often led to death after 2-5 weeks. Hearts showed myocardial necrosis of the right ventricular wall. Dehydroanacrotine, the putative reactive pyrrolic metabolite of anacrotine, given i.v. to rats, caused dose-related chronic lung and heart damage identical to that produced by anacrotine, but after lower doses (6-27 mg/kg); larger amounts caused acute lung damage. It is suggested that the severe lung damage in animals given anacrotine is due to dehydroanacrotine, formed in the liver. This metabolite is more stable than the pyrrolic derivatives of most other pyrrolizidine alkaloids, and it is thus able to reach the lungs in relatively large amounts.
对断奶雄性大鼠研究了阿那克罗丁（一种吡咯里西啶生物碱（PA），其结构为具有一个额外6 - 羟基的千里光碱）的作用。当腹腔注射阿那克罗丁（100毫克/千克）时，吡咯代谢物在最初0.5小时内在肝脏中达到峰值水平，然后迅速下降至较低水平，随后下降速度更慢。吡咯代谢物在最初一小时内在肺中积累至一定水平，然后至少4小时内保持相对稳定。给药2小时后，肺中吡咯代谢物水平约为肝脏水平的39%，而给予千里光碱的大鼠中这一比例为16%。当腹腔注射125毫克/千克或更高剂量时，阿那克罗丁会引起急性小叶中心坏死和肝脏充血，但口服剂量（高达180毫克/千克）引起的肝脏坏死相对较少。在随后几周内肝细胞肿大，但与通常与吡咯里西啶中毒相关的奇异巨细胞相比，这些肿大程度较轻。相比之下，阿那克罗丁比大多数其他吡咯里西啶生物碱造成的肺损伤要严重得多。腹腔注射或口服剂量远低于产生急性肝损伤所需剂量时，肺就会受到影响。给药后2天内出现肺充血和水肿、肺内皮广泛坏死以及肺泡间隔增厚。单次腹腔注射60毫克/千克或更高剂量后，肺组织的进行性实变通常会在2 - 5周后导致死亡。心脏显示右心室壁心肌坏死。脱氢阿那克罗丁（阿那克罗丁的假定反应性吡咯代谢物）静脉注射给大鼠时，会引起与阿那克罗丁产生的相同的剂量相关的慢性肺和心脏损伤，但剂量较低（6 - 27毫克/千克）；剂量更大时会引起急性肺损伤。有人认为，给予阿那克罗丁的动物中严重的肺损伤是由于在肝脏中形成的脱氢阿那克罗丁。这种代谢物比大多数其他吡咯里西啶生物碱的吡咯衍生物更稳定，因此能够以相对大量到达肺部。
