Wuya College of Innovation , Shenyang Pharmaceutical University , Shenyang , Liaoning 110016 , P.R. China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province , Guizhou Medical University , Guiyang , Guizhou 550025 , P.R. China.
Chem Res Toxicol. 2019 Jun 17;32(6):1281-1288. doi: 10.1021/acs.chemrestox.9b00081. Epub 2019 May 10.
Aloe-emodin (AE) is a major anthraquinone ingredient of numerous traditional Chinese medicines with a variety of beneficial biological activities in vitro. Previous studies suggested that AE possessed cytotoxicity and genotoxicity. Nevertheless, the mechanisms of the toxic action of AE have not yet been fully clarified. The present study aimed at characterization of metabolic pathways of AE to better understand the mechanisms of AE-induced cytotoxicity. An AE-derived glutathione conjugate (AE-GSH) was observed in rat liver cytosol incubations containing AE and GSH, along with 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Similar incubation fortified with N-acetylcysteine (NAC) in place of GSH offered an AE-NAC conjugate corresponding to the GSH conjugate. The formation of the two conjugates was found to require PAPS. The two conjugates were respectively detected in bile and urine of rats given AE. Sulfotransferase (SULT) inhibitor pentachlorophenol (PCP) suppressed the production of the observed AE-GSH/NAC conjugates in vivo, which suggested that SULTs participated in the process of the metabolic activation of AE. The presence of PCP attenuated cell susceptibility to AE-induced cytotoxicity. The present study illustrated potential association of sulfation-mediated bioactivation of AE with its cytotoxicity.
大黄酸（AE）是许多中药的主要蒽醌成分，具有多种有益的体外生物活性。先前的研究表明，AE 具有细胞毒性和遗传毒性。然而，AE 的毒性作用机制尚未完全阐明。本研究旨在对 AE 的代谢途径进行表征，以更好地了解 AE 诱导细胞毒性的机制。在含有 AE 和 GSH 以及 3'-磷酸腺苷-5'-磷酸硫酸（PAPS）的大鼠肝胞质孵育中观察到 AE 衍生的谷胱甘肽缀合物（AE-GSH），以及 3'-磷酸腺苷-5'-磷酸硫酸（PAPS）。类似的孵育用 N-乙酰半胱氨酸（NAC）代替 GSH 提供了与 GSH 缀合物对应的 AE-NAC 缀合物。发现两种缀合物的形成都需要 PAPS。在给予 AE 的大鼠的胆汁和尿液中分别检测到两种缀合物。磺基转移酶（SULT）抑制剂五氯苯酚（PCP）抑制了体内观察到的 AE-GSH/NAC 缀合物的产生，这表明 SULT 参与了 AE 的代谢激活过程。PCP 的存在减轻了细胞对 AE 诱导的细胞毒性的敏感性。本研究说明了磺化介导的 AE 生物活化与其细胞毒性之间的潜在关联。
