Transforming of Triptolide into Characteristic Metabolites by the Gut Microbiota.

Ran Peng,Yan Wang,Li-Bin Pan,Hang Yu,Pei Han,Jie Fu,Shu-Rong Ma,Zheng-Wei Zhang

doi:10.3390/molecules25030606

Abstract

The importance of the gut microbiota in drug metabolism, especially in that of nonabsorbable drugs, has become known. The aim of this study was to explore the metabolites of triptolide by the gut microbiota. With high-performance liquid chromatography coupled with tandem mass spectrometry and ion trap time-of-flight multistage mass spectrometry (LC-MS/MS and LC/MSn-IT-TOF), four metabolites of triptolide (M1, M2, M3, and M4) were found in the intestinal contents of rats. M1 and M2, were isomeric monocarbonyl-hydroxyl-substituted metabolites with molecular weights of 390. M3 and M4 were isomeric dehydrogenated metabolites with molecular weights of 356. Among the four metabolites, the dehydrogenated metabolites (M3 and M4) were reported in the gut microbiota for the first time. The metabolic behaviors of triptolide in the gut microbiota and liver microsomes of rats were further compared. The monocarbonyl-hydroxyl-substituted metabolites (M1 and M2) were generated in both systems, and another monohydroxylated metabolite (M5) was found only in the liver microsomes. The combined results suggested that the metabolism of triptolide in the gut microbiota was specific, with two characteristic, dehydrogenated metabolites. This investigation might provide a theoretical basis for the elucidation of the metabolism mechanism of triptolide and guide its proper application in clinical administration.

Highlights

Triptolide is an epoxy diterpene lactone extracted from the dried roots of the celastraceae plant, which is one of the main active ingredients of Tripterygium wilfordii Hook F
Our study focused on the metabolism of triptolide in gut microbiota
LC-MS/MS was used to determine the level of triptolide in the samples and validation results are provided in Supplementary Data Table S1

Summary

Introduction

Triptolide is an epoxy diterpene lactone extracted from the dried roots of the celastraceae plant, which is one of the main active ingredients of Tripterygium wilfordii Hook F. It has a number of pharmacological activities, including immunomodulation, anti-inflammatory, and antitumor activities. With the wide use of triptolide, many studies and clinical case reports have shown that it has toxic effects on organs such as the liver, kidney, spleen, gastrointestinal tract, and heart [4]. One of its most severe adverse effects observed in the clinical use is hepatotoxicity, Zhao et al

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