Table_2_28-Day Oral Chronic Toxicity Study of Arctigenin in Rats.DOCX

Arctium lappa (burdock) is the most popular daily edible vegetable in China and Japan because of its general health tonic effects. Previous studies focused on the beneficial role of Arctigenin but neglected its potential side-effects and toxicities. In the present study, the sub-chronic toxicity profile of Arctigenin following 28 days of consecutive exposure was investigated in rats. The results showed that during the drug exposure period, Arctigenin-12 mg/kg administration resulted in focal necrosis and lymphocytes infiltration of heart ventricular septal muscle cells. In the kidney cortical zone, the renal tubular epithelial cells were swollen, mineralized, and lymphocyte infiltrated. In the liver, the partial hepatocyte cytoplasm showed vacuolation and fatty changes, focal necrosis, and interstitial lymphocyte infiltration. In the rats that underwent 36 mg/kg/day administration, there was bilateral testis and epididymis atrophy. In the lung and primary bronchus, erythrocytes and edema fluid were observed. Changes of proestrus or estrus were observed in the uterus, cervix, and vagina intimal epithelial cells. Lymphocytic focal infiltration occurred in the prostate mesenchyme. The high dosage of Arctigenin only decreased the body weight at day 4. At the end of the recovery period, histopathological changes were irreversible, even after withdrawal of the drug for 28 days. Focal necrosis still existed in the heart ventricular septal muscle cells and hepatocytes. Lymphocyte infiltrations were observed in the heart, renal cortex, hepatocyte, and pancreas exocrine gland. Meanwhile, atrophy occurred in the testicles and pancreas. In addition, in the Arctigenin-12 mg/kg group, creatinine (CREA) and brain weight were both significantly increased. The toxicokinetical study demonstrated that Arctigenin accumulated in the organs of rats. The food consumption, hematological, and biochemical parameters were not associated with the above results. These contradictory results might result from the lesions induced by Arctigenin, which were not sufficiently serious to change the parameters. These results suggest that Arctium lappa should be consumed daily with caution because of the potential toxicity induced by Arctigenin. According to all results, the lowest observed adverse effect level (LOAEL) was induced by 12 mg/kg daily exposure to Arctigenin, and the No-observed-adverse-effect-level (NOAEL) should be lower than 12 mg/kg.

Arctium lappa（牛蒡）作为中国和日本最受欢迎的日常食用蔬菜，其普遍的养生功效广为人知。既往研究集中于探讨Arctigenin（牛蒡苷）的益处，却忽略了其潜在的副作用及毒性。在本研究中，我们针对连续28天暴露于Arctigenin后的亚慢性毒性进行了探讨。结果显示，在药物暴露期间，12 mg/kg剂量的Arctigenin导致心脏室间隔肌细胞发生局灶性坏死和淋巴细胞浸润。在肾脏皮质区域，肾小管上皮细胞出现肿胀、矿化及淋巴细胞浸润。肝脏中，部分肝细胞质出现空泡化及脂肪变性，局灶性坏死及间质淋巴细胞浸润。接受36 mg/kg/day剂量治疗的鼠类，其睾丸和附睾出现双侧萎缩。在肺和主支气管中观察到红细胞和水肿液。子宫、宫颈和阴道内膜上皮细胞观察到去卵巢期或发情期的变化。前列腺间质出现淋巴细胞局灶性浸润。高剂量Arctigenin仅在第四天降低了体重。在恢复期结束时，即使停药28天，病理学变化仍不可逆。心脏室间隔肌细胞和肝细胞中仍存在局灶性坏死。在心脏、肾脏皮质、肝细胞和胰腺外分泌腺中观察到淋巴细胞浸润。同时，睾丸和胰腺出现萎缩。此外，在12 mg/kg组中，肌酐（CREA）和脑重显著增加。毒代动力学研究表明，Arctigenin在鼠类器官中积累。食物消耗、血液学和生化参数与上述结果无关。这些矛盾的结果可能源于Arctigenin诱导的损伤，其程度尚不足以改变参数。这些结果提示，鉴于Arctigenin可能引起的毒性，Arctium lappa应谨慎每日食用。综合所有结果，Arctigenin每日12 mg/kg的暴露剂量诱导了最低观察到的有害效应水平（LOAEL），而未观察到有害效应水平（NOAEL）应低于12 mg/kg。