title: Metabolic Disposition of Luteolin Is Mediated by the Interplay of UDP-Glucuronosyltransferases and Catechol-O-Methyltransferases in Rats.
abstract: Luteolin partially exerts its biologic effects via its metabolites catalyzed by UDP-glucuronosyltransferases (UGTs) and catechol-O-methyltransferases (COMTs). However, the interplay of UGTs and COMTs in mediating luteolin disposition has not been well clarified. In this study, we investigated the glucuronidation and methylation pathways of luteolin mediated by the interplay of UGTs and COMTs in vivo and in vitro. A total of nine luteolin metabolites was detected in rat plasma and bile by liquid chromatography-tandem mass spectrometry, namely, three glucuronides, two methylated metabolites, and four methylated glucuronides. Luteolin-3'-glucuronide (Lut-3'-G) exhibited the highest systemic exposure among these metabolites. Kinetics studies in rat liver S9 fractions suggested two pathways, as follows: 1) Luteolin was glucuronidated to luteolin-7-glucuronide, luteolin-4'-glucuronide, and Lut-3'-G by UGTs, and then Lut-7-G was methylated to chrysoeriol-7-glucuronide and diosmetin-7-glucuronide by COMTs. 2) Alternatively, luteolin was methylated to chrysoeriol and diosmetin by COMTs, and then chrysoeriol and diosmetin were glucuronidated by UGTs to their respective glucuronides. The methylation rate of luteolin was significantly increased by the absence of glucuronidation, whereas the glucuronidation rate was increased by the absence of methylation, but to a lesser extent. In conclusion, two pathways mediated by the interplay of UGTs and COMTs are probably involved in the metabolic disposition of luteolin. The glucuronidation and methylation of luteolin compensate for each other, although glucuronidation is the predominant pathway.
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zeng
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Linlin
authors.initials: L
authors.lastname: Lu
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.).
authors.forename: Xinchun
authors.initials: X
authors.lastname: Wang
authors.affiliation: First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, PR China (L.W., Q.C., X.Z., X.W.); International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China (L.W., L.Z., L.L., M.H., Z.L.); Department of Pharmacy, Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, PR China (Q.L.); and College of Pharmacy, University of Houston, Houston, Texas (M.H.) liuzq@gzucm.edu.cn.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D047309:Flavones / Q000378:metabolism*; D005419:Flavonoids / Q000378:metabolism*; D020719:Glucuronides / Q000097:blood / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D047311:Luteolin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D053858:Metabolic Networks and Pathways; D008745:Methylation; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D047309:Flavones; D005419:Flavonoids; D020719:Glucuronides; D002394:Catechol O-Methyltransferase; D014453:Glucuronosyltransferase; D047311:Luteolin; C007054:chrysoeriol; C039602:diosmetin