Metabolism of 20(S)-Ginsenoside Rg₂ by Rat Liver Microsomes: Bioactivation to SIRT1-Activating Metabolites.

Li-Yuan Ma,Xiu-Wei Yang,Xin-Bao Yang,Hong-Ping Wang,Qi-Le Zhou

doi:10.3390/molecules21060757

Abstract

20(S)-Ginsenoside Rg2 (1) has recently become a hot research topic due to its potent bioactivities and abundance in natural sources such as the roots, rhizomes and stems-leaves of Panax ginseng. However, due to the lack of studies on systematic metabolic profiles, the prospects for new drug development of 1 are still difficult to predict, which has become a huge obstacle for its safe clinical use. To solve this problem, investigation of the metabolic profiles of 1 in rat liver microsomes was first carried out. To identify metabolites, a strategy of combined analyses based on prepared metabolites by column chromatography and ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was performed. As a result, four metabolites M1–M4, including a rare new compound named ginsenotransmetin A (M1), were isolated and the structures were confirmed by spectroscopic analyses. A series of metabolites of 1, MA–MG, were also tentatively identified by UPLC-Q-TOF/MS in rat liver microsomal incubate of 1. Partial metabolic pathways were proposed. Among them, 1 and its metabolites M1, M3 and M4 were discovered for the first time to be activators of SIRT1. The SIRT1 activating effects of the metabolite M1 was comparable to those of 1, while the most interesting SIRT1 activatory effects of M3 and M4 were higher than that of 1 and comparable with that of resveratrol, a positive SIRT1 activator. These results indicate that microsome-dependent metabolism may represent a bioactivation pathway for 1. This study is the first to report the metabolic profiles of 1 in vitro, and the results provide an experimental foundation to better understand the in vivo metabolic fate of 1.

Highlights

Worldwide public demand for ginseng, the roots and rhizomes of Panax ginseng C
Because the relative yield of M2 was higher in all metabolites, it might seem that epimerization of C20 -OH was the initial steps in 1 metabolism to produce M2, followed by a monooxygenation reaction to generate metabolite M1, so we propose that the metabolism pathway was that 20(S)-ginsenoside Rg2 was firstly converted to any intermediates and further converted to 20(R)-ginsenoside Rg2
The metabolic profiles of 20(S)-G-Rg2 (1) in a Rat liver microsomes (RLM) incubation system were qualitatively described for the first time

Summary

Introduction

Worldwide public demand for ginseng, the roots and rhizomes of Panax ginseng C. There are active chemical ingredients called ginseng saponins (ginsenosides) in ginseng, which has been reported to be responsible for ginseng’s biological activities which include immune enhancement, antioxidant and memory enhancement effects, the recovery of vital energy, the alleviation of fatigue, blood flow improvement, and promoting longevity [2,3,4]. (20(S)-G-Rg2 ; 1, Scheme 1) is a well-known bioactive saponin of the roots and rhizomes [5], and the stems/leaves [6,7] of ginseng as well as red ginseng [8], and it is abundantly available from natural sources like the stems/leaves of P. ginseng. Absorption, distribution, Molecules 2016, 21, 757; doi:10.3390/molecules21060757 www.mdpi.com/journal/molecules

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