title: Species- and gender-dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes.
abstract: Flavonoids occur naturally as glucosides and aglycones. Their common phenolic hydroxyl groups may trigger extensive UDP-glucuronosyltransferase (UGT)- catalysed metabolism. Unlike aglycones, glucosides contain glucose moieties. However, the influence of these glucose moieties on glucuronidation of glucosides and aglycones remains unclear. In this study, the flavonoid glucoside tilianin and its aglycone acacetin were used as model compounds. The glucuronidation characteristics and enzyme kinetics of tilianin and acacetin were compared using human UGT isoforms, liver microsomes and intestinal microsomes obtained from different animal species. Tilianin and acacetin were metabolized into different glucuronides, with UGT1A8 produced as the main isoform. Assessment of enzyme kinetics in UGT1A8, human liver microsomes and human intestinal microsomes revealed that compared with tilianin, acacetin displayed lower Km (0.6-, 0.7- and 0.6-fold, respectively), higher Vmax (20-, 60- and 230-fold, respectively) and higher clearance (30-, 80- and 300-fold, respectively). Furthermore, glucuronidation of acacetin and tilianin showed significant species- and gender-dependent differences. In conclusion, glucuronidation of flavonoid aglycones is faster than that of glucosides in the intestine and the liver. Understanding the metabolism and species- and gender-dependent differences between glucosides and aglycones is crucial for the development of drugs from flavonoids.
authors: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.|International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Peimin
authors: P
authors: Dai
authors: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Feifei
authors: F
authors: Luo
authors: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.|International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Ying
authors: Y
authors: Wang
authors: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Huangyu
authors: H
authors: Jiang
authors: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.|First Affiliated Hospital of the Medical College, Shihezi University, Xin Jiang, 832008, China.
authors: Liping
authors: L
authors: Wang
authors: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Guiyu
authors: G
authors: Zhang
authors: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Lijun
authors: L
authors: Zhu
authors: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.|Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, Texas, 77030, USA.
authors: Ming
authors: M
authors: Hu
authors: First Affiliated Hospital of the Medical College, Shihezi University, Xin Jiang, 832008, China.
authors: Xinchun
authors: X
authors: Wang
authors: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Linlin
authors: L
authors: Lu
authors: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.|International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
authors: Zhongqiu
authors: Z
authors: Liu
mesh_terms: D000818:Animals; D005260:Female; D047309:Flavones / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism*; D005960:Glucosides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006027:Glycosides / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology* / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D009928:Organ Specificity; D011994:Recombinant Proteins / Q000378:metabolism; D012737:Sex Factors; D013045:Species Specificity
chemical_list: D047309:Flavones; D005419:Flavonoids; D005960:Glucosides; D006027:Glycosides; D007527:Isoenzymes; D011994:Recombinant Proteins; C426884:tilianin; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8; C023717:acacetin
keywords: enzyme kinetics; flavonoids; glucuronidation; in vitro incubation