A combined strategy of mass fragmentation, post-column cobalt complexation and shift in ultraviolet absorption spectra to determine the uridine 5′-diphospho-glucuronosyltransferase metabolism profiling of flavones after oral administration of a flavone mixture in rats

Li, Qiang; Wang, Liping; Dai, Peimin; Zhang, Xuejun; Qi, Xiaoxiao; Zhu, Lijun; Yan, Tingting; Wang, Ying; Lu, Linlin; Hu, Ming; Wang, Xinchun; Liu, Zhongqiu

doi:10.1016/j.chroma.2015.03.069

Cited by 29 publications

(30 citation statements)

References 25 publications

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“…We already identified the metabolites of diosmetin and chrysoeriol in our previous study [16]. UHPLC—MS/MS analysis showed that two mono-glucuronides were formed in HLMs incubations with diosmetin and chrysoeriol in the presence of UDPGA.…”

Section: Resultsmentioning

confidence: 99%

“…It was reported that luteolin could be metabolized to diosmetin and chrysoeriol, which were the methylation metabolites. And the diosmetin and chrysoeriol could be metabolized in rats by Ugts [16]. Therefore, it was speculated that glucuronides of diosmetin and chrysoeriol would be formed in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Tilianin (95% purity; internal standard; IS) was provided by the Department of Pharmacy, First Hospital Affiliated to Shihezi University. Diosmetin-7-O-glucuronide (Dio-7-G), diosmetin-3′-O-glucuronide (Dio-3′-G), chrysoeriol-7-O-glucuronide (Chr-7-G) and chrysoeriol-4′-O-glucuronide (Chr-4′-G) were prepared and identified by our laboratory [16]. Carvacrol and troglitazone were purchased from Qiyun Bio-Technology Co. Ltd. (Guangzhou, China).…”

Section: Methodsmentioning

confidence: 99%

“…UGT isoforms involved in glucuronidation of phenolics and other relevant compounds discussed belong to UGT1A or UGT2B family [13], and these enzymes possess broad and overlapping substrate specificities. Our previous study demonstrated that diosmetin and chrysoeriol could be metabolized to their phase II metabolites by Ugts [16]. Thus, the UGT-catalyzed glucuronidation could play a key role in determining the bioavailability and clearance of diosmetin and chrysoeriol [13].…”

Section: Introductionmentioning

confidence: 99%

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Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

et al. 2016

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This study aimed to determine the reaction kinetics of the regioselective glucuronidation of diosmetin and chrysoeriol, two important methylated metabolites of luteolin, by human liver microsomes (HLMs) and uridine-5′-diphosphate glucuronosyltransferase (UGTs) enzymes. This study also investigated the effects of breast cancer resistance protein (BCRP) on the efflux of diosmetin and chrysoeriol glucuronides in HeLa cells overexpressing UGT1A9 (HeLa—UGT1A9). After incubation with HLMs in the presence of UDP-glucuronic acid, diosmetin and chrysoeriol gained two glucuronides each, and the OH—in each B ring of diosmetin and chrysoeriol was the preferable site for glucuronidation. Screening assays with 12 human expressed UGT enzymes and chemical-inhibition assays demonstrated that glucuronide formation was almost exclusively catalyzed by UGT1A1, UGT1A6, and UGT1A9. Importantly, in HeLa—UGT1A9, Ko143 significantly inhibited the efflux of diosmetin and chrysoeriol glucuronides and increased their intracellular levels in a dose-dependent manner. This observation suggested that BCRP-mediated excretion was the predominant pathway for diosmetin and chrysoeriol disposition. In conclusion, UGT1A1, UGT1A6, and UGT1A9 were the chief contributors to the regioselective glucuronidation of diosmetin and chrysoeriol in the liver. Moreover, cellular glucuronidation was significantly altered by inhibiting BCRP, revealing a notable interplay between glucuronidation and efflux transport. Diosmetin and chrysoeriol possibly have different effects on anti-cancer due to the difference of UGT isoforms in different cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

et al. 2016

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“…Although the determination of acacetin‐7‐glucuronide (Aca‐7‐G), a major glucuronidated metabolite of tilianin in rats, was previously performed using high‐performance liquid chromatography (HPLC) (Dai, Luo, et al, , Dai, Zhu, et al, ), the sensitivity of the HPLC method is not sufficient for the accurate determination of compounds present in trace concentrations. The determination of Aca‐7‐G in rat plasma using ultra‐high‐performance liquid chromatography with tandem mass spectrometry (UHPLC–MS/MS) after oral administration of Dracocephalum moldavica was studied (Li et al, ); however, reports on the sulfated metabolites of tilianin remain scarce. Flavonoids and their conjugated metabolites are usually eliminated by active efflux transporters located in the liver and intestine (Vlaming et al, ; Zhu, Xu, Wang, & Hu, ).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of tilianin and its metabolites in mice using ultra‐high‐performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study

Wang

Chen

Zhu

et al. 2017

Biomedical Chromatography

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Tilianin is an active flavonoid glycoside found in many medical plants. Data are lacking regarding its pharmacokinetics and disposition in vivo. The objective of this study was to develop a sensitive, reliable and validated ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method to simultaneously quantify tilianin and its main metabolites and to determine its pharmacokinetics in wild-type and breast cancer resistance protein knockout (Bcrp1-/-) FVB mice. Chromatographic separation was accomplished on a C column by utilizing acetonitrile and 0.5 mm ammonium acetate as the mobile phase. Mass spectrometric detection was performed using electrospray ionization in both positive and negative modes. The results showed that the precision, accuracy and recovery, as well as the stability of tilianin and its metabolites in mouse plasma, were all within acceptable limits. Acacetin-7-glucuronide and acacetin-7-sulfate were the major metabolites of tilianin in mouse plasma. Moreover, systemic exposure of acacetin-7-sulfate was significantly higher in Bcrp1 (-/-) FVB mice compared with wild-type FVB mice. In conclusion, the fully validated UHPLC-MS/MS method was sensitive, reliable, and was successfully applied to assess the pharmacokinetics of tilianin in wild-type and Bcrp1 (-/-) FVB mice. Breast cancer resistance protein had a significant impact on the elimination of the sulfated metabolite of tilianin in vivo.

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Chemical identification and quality evaluation of Lycopus lucidus Turcz by UHPLC‐Q‐TOF‐MS and HPLC‐MS/MS and hierarchical clustering analysis

Ren

Ding

Sun

et al. 2016

Biomedical Chromatography

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Lycopus lucidus Turcz has been used as a traditional phytomedicine for menstrual disorder, amenorrhea, menstrual cramps, inflammation and cardiovascular diseases. However, there is not enough information about identification and quantification for the chemical constituents of L. lucidus Turcz. In this work, a simple, rapid and sensitive UHPLC-Q-TOF-MS method was developed for characterization and identification of the phytochemical compositions in L. lucidus Turcz in negative ion mode. A total of 37 compounds, including 15 phenolic acids, 12 flavonoids, three triterpenoids and seven organic acids were tentatively characterized and identified by means of the retention time, accurate mass and characteristic fragment ions. Thirteen compounds were reported for the first time in L. lucidus Turcz. Among of them, 11 compounds were further quantified by multiple reactions monitoring. The results showed good performance with respect to linearity (r > 0.9959), repeatability (RSD < 2.6%), intra- and inter-day precision (RSD < 3.2%), recovery (93.1-104.9%), and lower limit of quantification (5-50 ng/mL). Subsequently, the results were analyzed and classified by hierarchical cluster analysis. The research could be applied for identification and quality evaluation for L. lucidus Turcz.

show abstract

A combined strategy of mass fragmentation, post-column cobalt complexation and shift in ultraviolet absorption spectra to determine the uridine 5′-diphospho-glucuronosyltransferase metabolism profiling of flavones after oral administration of a flavone mixture in rats

Cited by 29 publications

References 25 publications

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

Simultaneous determination of tilianin and its metabolites in mice using ultra‐high‐performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study

Chemical identification and quality evaluation of Lycopus lucidus Turcz by UHPLC‐Q‐TOF‐MS and HPLC‐MS/MS and hierarchical clustering analysis

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