title: Identification of glutathione and related cysteine conjugates derived from reactive metabolites of methyleugenol in rats.
abstract: Methyleugenol (ME), an alkenylbenzene compound, is a constituent of many foods and is used as flavoring agent in foodstuffs and as fragrance in cosmetics. It has been reported that exposure to ME can cause carcinogenicity, cytotoxicity, and genotoxicity. Metabolic activation is suggested to play an important role in ME-induced toxicities. Electrophilic metabolites of ME have been reported to covalently bind to proteins and nucleic acids. The objective of this study was to identify GSH and related cysteine conjugates derived from these reactive metabolites in vivo. Five biliary GSH (M1-M5) and four urinary cysteine conjugates (M6-M9) were detected in rats given ME. M1 and M2 were GSH conjugates derived from the epoxide of ME. M3, M4, and M5 were GSH conjugates possibly generated from the corresponding α,β-unsaturated aldehyde, carbonium ion, and quinone methide, respectively. The structures of the GSH conjugates were verified by chemical synthesis. Cysteine conjugates M6, M7, M8, and M9 were found to correspond to the respective M1/M2, M3, M4, and M5. The data obtained from the present in vivo work facilitate the understanding of mechanism action of ME toxicities and may provide information suitable for use as biomarkers of exposure to ME.
authors.affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
authors.forename: Huina
authors.initials: H
authors.lastname: Yao
authors.affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: yingpeng1999@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, 98101, USA. Electronic address: zhengneu@yahoo.com.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry*; D005054:Eugenol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: C005223:methyleugenol; D005054:Eugenol; D005978:Glutathione; D003545:Cysteine
keywords: Cysteine conjugates; Glutathione conjugates; Mechanism action; Metabolic activation; Methyleugenol; Reactive metabolites