Abstract
GL-V9 is a prominent derivative of wogonin with a wide therapeutic spectrum and potent anti-tumor activity. The metabolism characteristics of GL-V9 remain unclear. This study aimed to clarify the metabolic pathway of GL-V9 and investigate the generation of its glucuronidation metabolites in vitro and in vivo. HPLC-UV-TripleTOF was used to identify metabolites. The main metabolite that we found was chemically synthesized and the synthetic metabolite was utilized as standard substance for the subsequent metabolism studies of GL-V9, including enzyme kinetics in liver microsomes of five different species and reaction phenotyping metabolism using 12 recombinant human UDP-glucuronosyltransferase (UGT) isoforms. Results indicated that the glucuronidation reaction occurred at C5-OH group, and 5-O-glucuronide GL-V9 is the only glucuronide metabolite and major phase II metabolite of GL-V9. Among 12 recombinant human UGTs, rUGT1A9 showed the strongest catalytic capacity for the glucuronidation reaction of GL-V9. rUGT1A7 and rUGT1A8 were also involved in the glucuronidation metabolism. Km of rUGT1A7-1A9 was 3.25 ± 0.29, 13.92 ± 1.05, and 4.72 ± 0.28 μM, respectively. In conclusion, 5-O-glucuronide GL-V9 is the dominant phase II metabolite of GL-V9 in vivo and in vitro, whose formation rate and efficiency are closely related to isoform-specific metabolism profiles and the distribution of UGTs in different tissues of different species.
Highlights
Flavonoids as a large subgroup of phenolic metabolites that are widely present in plants used as folk medicines [1]
HPLC-UV-TripleTOF analysis indicated that glucuronidation conjugates were formed in the Molecules 2019, 24, x FOR PEER REVIEW
Glucuronidation is a vital pathway for metabolism and clearance of flavonoids and their their derivatives containing phenolic hydroxyl groups and/or methoxy groups [39]
Summary
Flavonoids as a large subgroup of phenolic metabolites that are widely present in plants used as folk medicines [1]. They are found in tea, wine [2], propolis and honey [3], and commonly account for a major component of human diet [4]. Flavonoids and their derivatives have been considered as potential therapeutic compounds for a multitude of diseases because of their wide range of biological and pharmacological activities, including oestrogenic activity [5], anti-inflammatory activity [6], antioxidant activity [7], antiallergic activity [8,9], anti-tumor activity [10,11] and vascular regulation activity [12,13]. This explains the fact that only a few Molecules 2019, 24, 1576; doi:10.3390/molecules24081576 www.mdpi.com/journal/molecules
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