Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, 6439 Garners Ferry Rd., Columbia, SC, 29209, USA.
Department of Chemistry and Biochemistry, College of Arts and Sciences, University of South Carolina, Columbia, SC, 29208, USA.
BMC Pharmacol Toxicol. 2021 Jan 28;22(1):9. doi: 10.1186/s40360-021-00474-1.
Emodin, a natural anthraquinone, has shown potential as an effective therapeutic agent in the treatment of many diseases including cancer. However, its clinical development is hindered by uncertainties surrounding its potential toxicity. The primary purpose of this study was to uncover any potential toxic properties of emodin in mice at doses that have been shown to have efficacy in our cancer studies. In addition, we sought to assess the time course of emodin clearance when administered both intraperitoneally (I.P.) and orally (P.O.) in order to begin to establish effective dosing intervals.
We performed a subchronic (12 week) toxicity study using 3 different doses of emodin (~ 20 mg/kg, 40 mg/kg, and 80 mg/kg) infused into the AIN-76A diet of male and female C57BL/6 mice (n = 5/group/sex). Body weight and composition were assessed following the 12-week feeding regime. Tissues were harvested and assessed for gross pathological changes and blood was collected for a complete blood count and evaluation of alanine transaminase (ALT), aspartate transaminase (AST) and creatinine. For the pharmacokinetic study, emodin was delivered intraperitoneally I.P. or P.O. at 20 mg/kg or 40 mg/kg doses to male and female mice (n = 4/group/sex/time-point) and circulating levels of emodin were determined at 1, 4 and 12 h following administration via liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis.
We found that 12 weeks of low (20 mg/kg), medium (40 mg/kg), or high (80 mg/kg) emodin feeding did not cause pathophysiological perturbations in major organs. We also found that glucuronidated emodin peaks at 1 h for both I.P. and P.O. administered emodin and is eliminated by 12 h. Interestingly, female mice appear to metabolize emodin at a faster rate than male mice as evidenced by greater levels of glucuronidated emodin at the 1 h time-point (40 mg/kg for both I.P. and P.O. and 20 mg/kg I.P.) and the 4-h time-point (20 mg/kg I.P.).
In summary, our studies establish that 1) emodin is safe for use in both male and female mice when given at 20, 40, and 80 mg/kg doses for 12 weeks and 2) sex differences should be considered when establishing dosing intervals for emodin treatment.
大黄素是一种天然蒽醌，已显示出作为治疗多种疾病（包括癌症）的有效治疗剂的潜力。然而，其临床开发受到其潜在毒性的不确定性的阻碍。本研究的主要目的是在已显示对我们的癌症研究有效的剂量下，发现大黄素在小鼠体内的任何潜在毒性作用。此外，我们试图评估腹腔内（I.P.）和口服（P.O.）给予大黄素时的清除时间过程，以便开始建立有效的给药间隔。
我们使用 3 种不同剂量的大黄素（~20mg/kg、40mg/kg 和 80mg/kg）对雄性和雌性 C57BL/6 小鼠的 AIN-76A 饮食进行了为期 12 周的亚慢性（12 周）毒性研究（n=5/组/性别）。在 12 周的喂养期后，评估体重和体重组成。采集组织，评估大体病理变化，并采集血液进行全血细胞计数和丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和肌酐评估。对于药代动力学研究，雄性和雌性小鼠（n=4/组/性别/时间点）以 20mg/kg 或 40mg/kg 剂量腹腔内（I.P.）或口服（P.O.）给予大黄素，并通过液质联用（LC-MS/MS）分析在给药后 1、4 和 12 小时测定大黄素的循环水平。
我们发现，12 周低（20mg/kg）、中（40mg/kg）或高（80mg/kg）大黄素喂养不会引起主要器官的病理生理改变。我们还发现，腹腔内和口服给予的大黄素的葡萄糖醛酸化大黄素在 1 小时时达到峰值，并在 12 小时时消除。有趣的是，雌性小鼠似乎比雄性小鼠更快地代谢大黄素，证据是在 1 小时（腹腔内和口服给药的 40mg/kg 和腹腔内给药的 20mg/kg）和 4 小时（腹腔内给药的 20mg/kg）时葡萄糖醛酸化大黄素水平更高。
总之，我们的研究表明，1）当以 20、40 和 80mg/kg 剂量给药 12 周时，大黄素在雄性和雌性小鼠中使用是安全的，2）在确定大黄素治疗的给药间隔时应考虑性别差异。
