Sulfonation Disposition of Acacetin: In Vitro and in Vivo

Zhang, Qisong; Zhu, Lijun; Gong, Xia; Ruan, Yanjiao; Yu, Jia; Jiang, Hongbin; Wang, Ying; Qi, Xiaoxiao; Lu, Linlin; Liu, Zhong Qiu

doi:10.1021/acs.jafc.7b00854

Cited by 16 publications

(10 citation statements)

References 48 publications

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“…We concluded that BCRP had a significant impact on the elimination of Aca‐7‐S in vivo . This conclusion was supported by a previous report showing that Aca‐7‐S was transported primarily by BCRP and MRP1 in vivo (Zhang et al, ). In addition, BCRP was probably involved in the elimination of Aca‐7‐G but was not the major determinant.…”

Section: Resultssupporting

confidence: 84%

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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Section: Resultssupporting

confidence: 84%

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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“…The molecular formulas were assigned as C 16 H 12 O 8 S, 80 Da (SO 3 ) larger than that of the parent drug. The MS 2 spectra of M14 and M15 presented staple ions at m / z 283.0607 and 268.0369 by continuously dropping SO 3 and CH 3; since their Clog P values were 1.02632 and 1.92632, which were calculated by ChemDraw 14.0, M14 and M15 were respectively identified as acacetin-5- O -sulfate and acacetin-8- O -sulfate …”

Section: Resultsmentioning

confidence: 99%

“…In addition, the liver microsome system has been regarded as a valuable model to study food and drug metabolism in vitro due to the biotransformation organ of the liver . Previously, the monoglucuronide and monosulfate metabolites of acacetin were identified, and their dispositions were investigated. , Nevertheless, to date, no systematic and detailed metabolite data are available, particularly those of acacetin. Therefore, it is indispensable to clarify the metabolites of acacetin.…”

Section: Introductionmentioning

confidence: 99%

A Systematic Study of the Metabolites of Dietary Acacetin in Vivo and in Vitro Based on UHPLC-Q-TOF-MS/MS Analysis

Yin

Liang

et al. 2019

J. Agric. Food Chem.

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Acacetin, a dietary component, is abundant in acacia honey and has superior anticancer activities. To date, no research on the metabolism of acacetin has been reported. In the current research, an online detection strategy of ultra-highperformance liquid chromatography connected to a quadrupole time-of-flight mass spectrometer (UHPLC-Q-TOF-MS/MS) was utilized for metabolite identification in vivo (rat plasma, bile, urine, and feces) and in vitro (rat liver microsomes). A total of 31 metabolites were structurally characterized in rats, and 25 metabolites were detected in rat liver microsomes, among which, 4 metabolites were compared with standards. Oxidation, the loss of CH 2 , reduction, hydrolysis, glucuronide conjugation, sulfate conjugation, methylation, and N-acetylation were the main metabolic pathways of acacetin. This study is the first to characterize acacetin metabolites in vivo and in vitro, and the results of this study offer novel and valuable evidence for a comprehensive understanding of the safety and efficacy of acacetin.

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“…The reversibility of MAO-B inhibition with acacetin 7-methyl ether adds significant value to its potential therapeutic use. A recent pharmacokinetics study of acacetin metabolism in vitro and in vivo that analysed its metabolites showed that acacetin is metabolized by the sulfotransferase 1A1 enzyme into acacetin-7-sulfate, which was detected in vivo in plasma samples and also in vitro from incubation of the Liver S9 fraction [29].…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)

et al. 2019

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The investigation of the constituents that were isolated from Turnera diffusa (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC50 = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4′, 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC50 = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC50 for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., SelegilineTM or ZelaparTM, a selective MAO-B inhibitor), acacetin 7-methyl ether’s selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson’s disease.

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Sulfonation Disposition of Acacetin: In Vitro and in Vivo

Cited by 16 publications

References 48 publications

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

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

A Systematic Study of the Metabolites of Dietary Acacetin in Vivo and in Vitro Based on UHPLC-Q-TOF-MS/MS Analysis

Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)

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