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Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes
Author(s) -
Dai Peimin,
Luo Feifei,
Wang Ying,
Jiang Huangyu,
Wang Liping,
Zhang Guiyu,
Zhu Lijun,
Hu Ming,
Wang Xinchun,
Lu Linlin,
Liu Zhongqiu
Publication year - 2015
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1989
Subject(s) - acacetin , glucuronidation , aglycone , chemistry , microsome , glucoside , biochemistry , enzyme , flavonoid , glucuronosyltransferase , metabolism , stereochemistry , glycoside , antioxidant , apigenin , medicine , alternative medicine , pathology
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 K m (0.6‐, 0.7‐ and 0.6‐fold, respectively), higher V max (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. Copyright © 2015 John Wiley & Sons, Ltd.