In Vitro Study of UGT Metabolism and Permeability of Orientin and Isoorientin, Two Active flavonoid C-glycosides.

Abstract

C-glycosides are important flavonoids with significant pharmacological activities implicated in anticancer and antioxidative effects. However, their characteristics of metabolism and transportation have been rarely investigated. This research aimed to examine the metabolic characteristics of two active C-glycosides, namely, orientin and isoorientin, in human liver microsomes (HLMs) and rat liver microsomes (RLMs) and to confirm the specific uridine 5'-diphospho glucuronosyltransferase (UGT) isoforms involved in glucuronidation by HLMs. Furthermore, the permeability of orientin and isoorientin was also determined by using Caco-2 cell monolayers. Results revealed that orientin and isoorientin could generate two metabolites, which were identified as monoglucuronides. HLM- and RLM-mediated glucuronide formations were in accordance with typical Michaelis-Menten kinetics. Conversely, RLM initially metabolized orientin to its corresponding metabolite, and this process was consistent with biphasic kinetics. Among the UGT isoform, UGT1A1, 1A8, 1A9 and 1A10 exhibited the highest enzyme activity. Passive diffusion was the predominant orientin and isoorientin transportation mechanism in Caco-2 cell monolayers, and their apparent permeability further confirmed that orientin and isoorientin were well absorbed. Therefore, orientin and isoorientin can be metabolized by UGT isoforms and microsomes; these flavonoids can also be transported via passive diffusion in Caco-2 cells, which are relatively permeable.