College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
J Agric Food Chem. 2016 Jul 20;64(28):5742-50. doi: 10.1021/acs.jafc.6b01872. Epub 2016 Jul 12.
Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human.
大黄等多种药用植物的主要成分是大黄酸。尽管大黄酸的应用广泛，但含大黄酸的草药中毒的病例时有报道。本研究旨在探讨大黄酸是否会发生代谢激活从而产生毒性。在与不同种属的肝微粒体孵育后，鉴定出三种大黄酸单葡萄糖醛酸苷，分别对应于两个羟基葡萄糖醛酸苷和一个通过羧基形成的酰基葡萄糖醛酸苷。进一步的研究表明，大黄酸酰基葡萄糖醛酸苷具有化学反应活性，并对肝癌细胞表现出细胞毒性。此外，在实验动物和人体之间观察到大黄酸葡萄糖醛酸化存在明显的种属差异。反应表型实验表明，大黄酸酰基葡萄糖醛酸苷主要由尿苷 5'-二磷酸葡萄糖醛酸基转移酶 1A1、1A9 和 2B7 催化。综上所述，本研究证实大黄酸可通过形成酰基葡萄糖醛酸苷发生代谢激活，尤其在人体中。
