title: Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs.
abstract: 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.
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
authors.forename: Jiyue
authors.initials: J
authors.lastname: Zheng
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Ruan
authors.affiliation: College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010936:Plant Extracts / Q000378:metabolism* / Q000633:toxicity; D012250:Rheum / Q000737:chemistry*
chemical_list: D000880:Anthraquinones; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D014453:Glucuronosyltransferase; C020491:rhein
keywords: acyl glucuronide; metabolic activation; rhein