返魂草素Ⅱ对SD大鼠连续灌胃4周的重复给药毒性研究

Evaluation of Subchronic Toxicity of Senecio Cannabifolius Less. Ⅱ After 4-Week Repeated Intragastric Administration in SD rats

关键词:  返魂草素Ⅱ  重复给药  肝脏毒性

Key words:  Senecio Cannabifolius Less. Ⅱ  repeated administration  toxicity

摘要:

目的 研究返魂草的有效成分返魂草素Ⅱ重复灌胃给药4周对SD大鼠产生的毒性反应。方法 120只SD大鼠按体质量随机分为返魂草素Ⅱ低、中、高剂量组（药剂量分别为175，350，700 mg·kg^-1）和溶媒对照组（0.5% CMC-Na），每组30只，♀♂各半，给药体积均为10 mL·kg^-1。每天给药1次，共给药4周，给药结束每组剖检2/3大鼠，恢复2周后，剖检剩余的1/3大鼠，剖检时对各项毒理学指标进行检测。结果 在给药期间，各剂量组大鼠无死亡。低剂量组大鼠的一般行为、活动、毛发、大小便等均未见明显异常；中剂量组和高剂量组大鼠给药后出现流涎、腹部膨隆、食欲下降等症状，伴随活动减少，给药结束后逐渐恢复，症状的发生频率、持续时间和严重程度随剂量的降低呈降低趋势。给药过程中，返魂草素Ⅱ处理可导致中、高剂量组大鼠的食量和体质量在部分时间点低于溶媒对照组。血液生化指标检测结果显示，返魂草素Ⅱ处理主要导致高剂量组大鼠的ALT升高，TP和ALB降低，其他血液生化指标未见与药物处理相关的改变。脏器质量检查结果显示，返魂草素Ⅱ可导致高剂量组大鼠胸腺质量降低、肝脏质量降低和肾脏质量升高。病理组织学检查发现，给药结束时，返魂草素Ⅱ中剂量组和高剂量组的肝脏出现孤立性或多发性局灶性溶解坏死，病灶数目和病变严重程度呈现一定的剂量依赖性。恢复2周后，病灶检出数明显减少，病变程度明显减轻。其他器官未见明显与药物相关的改变。血液学和骨髓细胞检查等方面均未见明显的与返魂草素Ⅱ处理相关的改变。结论 返魂草素Ⅱ（700，350，175 mg·kg^-1）灌胃给药4周，毒性靶部位主要是消化系统（肝脏、胃肠道、食欲和体质量等），毒性剂量为700，350 mg·kg^-1时仍出现毒性反应。

Abstract:

OBJECTIVE To evaluate the toxicity of Senecio Cannabifolius Less. Ⅱ, an active ingredient of Senecio Cannabifolius Less., in SD rats following repeated intragastric administration for 4 weeks. METHODS One hundred and twenty SD rats were randomly divided into 4 groups with 30 animals (15 male and 15 female) in each group. Rats were treated orally once a day for 4 weeks with Senecio Cannabifolius Less. Ⅱ (175, 350, 700 mg·kg^-1) or 0.5% CMC-Na as vehicle with a volume of 10 mL·kg^-1. Two-thirds rats in each group were necropsied, and 2 weeks later, the one-third rats in each group were necropsied. During the necropsy, toxicological indexes were detected. RESULTS All the rats survived to scheduled necropsies. Sialorrhea, abdominal distention, anorexia and hypoactivity, inversely related to the duration of dosing, were observed in middle and high dose rats, with a dose-independent manner. Senecio Cannabifolius Less. Ⅱ (350, 700 mg·kg^-1) administration induced a clear trend of declining body weight gain and food intake, compared with the control group. There were no apparent clinical signs of toxicity observed in low dose rats and control rats. High dose rats showed significantly higher ALT, lower TP and ALB compared with control group. Lower thymus and liver, and higher kidney weights occurred mainly in high dose group. Histopathologic examination found that isolated or multiple focal lytic necroses were pronounced in mid-and high-dose rats, at the end of administration. These changes were released after a 2-week drug-free rest period. No other significant changes were observed in electrocardiogram, hematology and bone marrow examination in each group. CONCLUSION The main toxic target of Senecio Cannabifolius Less. Ⅱ is digestive system (increased liver, gastrointestinal tract, body weight and food intake). The toxicity dose of Senecio Cannabifolius Less. Ⅱ was 700, 350 mg·kg^-1.