山豆根醇沉物小鼠单次给药和大鼠重复给药28d毒性评价

Toxicity studies of alcohol precipitation from extracts of Radix sophorae tonkinensis after single dose administraion in mice and 28 days repeated dose administraion in rats

目的:研究山豆根醇沉物对小鼠单次给药及大鼠重复给药的毒性反应及特点。方法:以40m L·kg^(-1)给药量灌胃(ig)给予昆明种小鼠最大浓度(0. 4 g·mL^(-1))醇沉物混悬液,若出现死亡则按比例稀释,探讨最大耐受量(MTD)。Wistar大鼠连续ig给药28 d低剂量、中剂量和高剂量的醇沉物(相当于生药3. 5,14和42 g·kg^(-1),为临床常用剂量的3. 5,14和42倍),同时分别给予水提全组分(相当于生药14 g·kg^(-1))和等容量去离子水作为阳性对照和空白对照。每天给药观察,记录临床症状和死亡情况。每周称体重、摄食量,d 28解剖,进行血清生化、脏器指数及病理学检查。结果:小鼠MTD> 16 g·kg^(-1)(相当于生药202. 5g·kg^(-1))。山豆根醇沉物可抑制大鼠体重及摄食,唾液、粪便增多,重复给予高剂量醇沉物可造成谷丙转氨酶(ALT)、碱性磷酸酶(ALP)、总胆汁酸(TBA)、胆固醇(CHOL)和低密度脂蛋白(LDL-C)升高,而天门冬氨酸转氨酶(AST)、总胆红素(TBIL)、谷氨酸脱氢酶(GLDH)、肌酸激酶(CK)、尿酸(UA)变化不显著。肝脏指数及肝脑比升高,病理组织学检测偶见汇管区胆管增生、炎症浸润及脂质沉积。结论:山豆根醇沉物小鼠MTD> 16 g·kg^(-1)生药剂量,重复ig给予高剂量醇沉物可造成大鼠肝脏毒性及血脂相关生化指标升高。山豆根醇沉物毒性低于水提全组分,对心脏和肾无毒性反应,临床用药应重点关注肝脏功能及血脂指标的变化。

Objective:To investigate the toxic effects and characteristics of alcohol precipitation from extracts of Radix sophorae tonkinensis after single dose administraion in mice and repeated dose administraion in rats.Methods:The alcohol precipitation suspension with maximum concentration(0.4 g·mL-1)was administered orally to Kunming mice at a dosage of 40 mL·kg-1.If death occurred,the suspension would be diluted in definite proportions so as to explore the maximum tolerance dose(MTD).Wistar rats were given low,medium and high dose of alcohol precipitation by gavage for 28 days at dosages of 3.5,14 and 42 g·kg-1 crude drug,respectively,which were correspondingly 3.5,14 and 42 times of the usual clinical doses.Meanwhile,the extracts of Radix sophorae tonkinensis(equivalent to 14 g·kg-1 crude drug)and equal volume of deionized water were respectively used as positive control and blank control.General observation was conducted,and clinical signs and mortality were recorded daily.Besides,the rats were weekly weighed and their food consumptions were also recorded.Onday 28,the rats were dissected to conduct serum biochemistry,organ index and pathological examination.Results:MTD in mice was greater than 16 g·kg-1(equivalent to 202.5 g·kg-1 crude drug).The alcohol precipitation induced the inhibition of body weights and food consumption of rats as well as increase of saliva secretion and excretion.Long-term high-dose administration led to the increase of glutamate pyruvic transaminase(ALT),alkaline phosphatase(ALP),total bile acid(TBA),cholesterol(CHOL)and low-density lipoprotein cholesterol(LDL-C).Aspartate aminotransferase(AST),total bilirubin(TBIL),glutamate dehydrogenase(GLDH),creatine kinase(CK),and uric acid(UA),however,did not change significantly.Besides,it also raised the ratios of liver and brain as well as liver index.Additionally,pathological examination occasionally observed ductular proliferation,inflammatory infiltration and lipoidosis in portal area.Conclusion:The MTD of alcohol precipitation from extracts of Radix sophorae tonkinensis in mice is greater than 16 g·kg-1.High-dose repeated administration orally can lead to hepatotoxicity and increase of serum lipid-related biochemical items.The alcohol precipitation has less toxicity than extracts of Radix sophorae tonkinensis,and has a nontoxic effect on heart and kidney.The results indicate that we should pay more attention to the changes in liver function and blood lipid in clinical drug use.