Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
Fitoterapia. 2019 Jul;136:104161. doi: 10.1016/j.fitote.2019.04.016. Epub 2019 Apr 30.
Ailanthone (AIL) has many biological activities including antimalarial, antiviral and anticancer. Our previous study also found that AIL targets p23 against castration-resistant prostate cancer. In this report, the preclinical safety of AIL was evaluated by acute toxicity, subacute toxicity and toxicokinetics in mice. In the acute toxicity study, the LD of AIL was 27.3 mg/kg, and severe pathological damages were mainly found in the liver and gastrointestinal tract. In the subacute toxicity study, mice were orally administered at doses of 2.5, 5 and 10 mg/kg for 28 days. The results showed the body weight of male mice in the 10 mg/kg dose group decreased, but that of female mice increased. Biochemical and histopathological analysis showed that AIL could cause steatohepatitis, splenomegaly, gastrointestinal mucosal damage and reproductive system abnormalities. In addition, AIL presented the reversible hematotoxicity. To determine the relationship between AIL toxicity and dose/exposure in vivo, toxicokinetics of AIL were carried out after a single oral dose of 15 mg/kg. The stomach was identified as the main target organ, followed by the intestine and kidney. On the basis of this study, the dose of 2.5 mg/kg had no adverse effect on mice. To sum up, this study is the first time to evaluate the systemic toxicity of AIL, which is useful for the further development of AIL.
苦木苦味素（AIL）具有抗疟、抗病毒和抗癌等多种生物活性。我们之前的研究还发现，AIL 以 p23 为靶点，针对去势抵抗性前列腺癌。在本报告中，通过急性毒性、亚急性毒性和毒代动力学研究在小鼠中评估了 AIL 的临床前安全性。在急性毒性研究中，AIL 的 LD 为 27.3mg/kg，主要发现严重的病理损伤主要发生在肝脏和胃肠道。在亚急性毒性研究中，小鼠连续 28 天口服 2.5、5 和 10mg/kg 的剂量。结果表明，10mg/kg 剂量组雄性小鼠的体重下降，但雌性小鼠的体重增加。生化和组织病理学分析表明，AIL 可引起肝脂肪变性、脾肿大、胃肠道黏膜损伤和生殖系统异常。此外，AIL 还表现出可逆的血液毒性。为了确定 AIL 毒性与体内剂量/暴露的关系，在单次口服 15mg/kg 后进行了 AIL 的毒代动力学研究。胃被确定为主要靶器官，其次是肠和肾。基于这项研究，2.5mg/kg 的剂量对小鼠没有不良影响。总之，这项研究首次评估了 AIL 的全身毒性，这对 AIL 的进一步开发很有帮助。
