title: Chemical Reactivity of Emodin and Its Oxidative Metabolites to Thiols.
abstract: Polygonum multiflorum is an herbal medicine widely employed in China. Hepatotoxicity of the herbal medicine has been well documented, but the mechanisms of the toxicity remain unknown. Emodin (EM) is a major constituent of the herb and has been reported to be hepatotoxic. The main purpose of this study was to define the metabolic pathways of EM in order to characterize the potential reactive intermediates. EM was incubated with rat liver microsomes or human liver microsomes, followed by LC-MS/MS analysis to investigate the in vitro and in vivo metabolism of EM. As a result, three monohydroxylation metabolites (M1-M3) were detected after exposure to EM: ω-hydroxyemodin, 2-hydroxyemodin, and 5-hydroxyemodin. Urinary M1 and M2 were detected in rats administered EM. Three mercapturic acids (M4-M6) were found in microsomal incubations containing EM, NADPH, and N-acetylcysteine. It appears that M4 originated from parent compound EM, and M5 and M6 originated from M1 and M2, respectively. Two biliary EM-derived GSH conjugates were found in EM-treated rats. One arose from direct adduction of EM with GSH, and the other was derived from M1. Cytochrome P450's 1A2, 2C19, and 3A4 were the predominant P450 enzymes to oxidize EM. The findings helped us to understand the mechanisms of EM-induced hepatotoxicity.
authors.forename: Boyang
authors.initials: B
authors.lastname: Qin
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Jiaming
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University , Guiyang, Guizhou 550004, P. R. China.
authors.forename: Jiang
authors.identifier: 0000-0002-0340-0275
authors.initials: J
authors.lastname: Zheng
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D004642:Emodin / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D013438:Sulfhydryl Compounds; D004642:Emodin