Safety of natural anthraquinone emodin: an assessment in mice

Abstract

Background 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. Methods 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. Results 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.). Conclusions 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.

Polygonum cuspidatum Extract (Pc-Ex) Containing Emodin Suppresses Lung Cancer-Induced Cachexia by Suppressing TCF4/TWIST1 Complex-Induced PTHrP Expression

“…Emodin (1,3,8-trihydroxy-6-methylanthraquinone) exerts multiple pharmacological effects, including anti-allergic, anti-osteoporotic, anti-diabetic, neuroprotective, hepatoprotective, cardioprotective, and anti-cancer effects [ 55 , 56 ], on various chronic diseases. A pre-clinical pharmacokinetic study has demonstrated the safety of emodin in mice [ 57 ]. Treatment with low (20 mg/kg body weight), medium (40 mg/kg body weight), or high (80 mg/kg body weight) doses of emodin for 12 weeks did not affect the physiology of major organs, such as the kidneys and liver.…”

The Health Benefits of Emodin, a Natural Anthraquinone Derived from Rhubarb—A Summary Update

“…The activity of emodin and its derivatives is related to their influence on inflammatory processes and their immunomodulatory activity [29]. Because of the uncertainty about the safety of using emodin for pharmacotherapy, in vivo studies in mice have been carried out to establish its safe dosage [30]. The results showed that administration of emodin at the doses of 20, 40, and 80 mg/kg for 12 weeks is safe and did not cause any The activity of emodin and its derivatives is related to their influence on inflammatory processes and their immunomodulatory activity [29].…”

“…The results showed that administration of emodin at the doses of 20, 40, and 80 mg/kg for 12 weeks is safe and did not cause any The activity of emodin and its derivatives is related to their influence on inflammatory processes and their immunomodulatory activity [29]. Because of the uncertainty about the safety of using emodin for pharmacotherapy, in vivo studies in mice have been carried out to establish its safe dosage [30]. The results showed that administration of emodin at the doses of 20, 40, and 80 mg/kg for 12 weeks is safe and did not cause any pathophysiological disorders in major organs in mammals.…”

“…Souginnis et al [30] evaluated the in vivo toxicity of emodin administered orally and intraperitoneally to mice in doses that have been shown to be efficient in cancer studies: 20 mg/kg, 40 mg/kg and 80 mg/kg, applied for 12 weeks. The levels of glucuronidated emodin in the blood of mice were measured.…”

Overview of Viral Pneumonia Associated With Influenza Virus, Respiratory Syncytial Virus, and Coronavirus, and Therapeutics Based on Natural Products of Medicinal Plants

“…As for their toxicity, cohort genotoxic studies have elucidated that glycyrrhizin is neither teratogenic nor mutagenic and may have properties of anti-genotoxic under the certain conditions; nonetheless, being continuously exposed to glycyrrhizin compounds at high concentration it can produce hypermineralocorticoid-like effects in both animals and humans ( Isbrucker and Burdock, 2006 ). Another compound emodin has been proven to possess laxative effects leading to melanosis, but only at very high doses, for example, 1–3 g/kg/d for mice ( Sougiannis et al, 2021 ). High dose of emodin can also result in mutagenic or hepatotoxicity by blocking the UGT1A1 enzyme activity ( Wang et al, 2016 ).…”