Generic placeholder image

Current Pharmaceutical Analysis


ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

The Metabolism of Tanshinone IIA, Protocatechuic Aldehyde, Danshensu, Salvianolic Acid B and Hydroxysafflor Yellow A in Zebrafish

Author(s): Ya-Li Wang, Shi-Jun Yin, Feng-Qing Yang, Guang Hu*, Guo-Can Zheng and Hua Chen*

Volume 17, Issue 1, 2021

Published on: 16 July, 2019

Page: [106 - 118] Pages: 13

DOI: 10.2174/1573412915666190716164035

Price: $65


Background: Tanshinone IIA (TIIA), protocatechuic aldehyde (PA), danshensu (DSS), salvianolic acid B (SAB) and hydroxysafflor yellow A (HSYA) are the major components of Salvia miltiorrhiza Bge. (Danshen) and Carthamus tinctorius L. (Honghua) herbal pair. These active components may contribute to the potential synergistic effects of the herbal pair.

Objective: This study aimed to investigate the metabolites of TIIA, PA, DSS, SAB and HSYA in zebrafish, and to explore the influence of HSYA on the metabolism of TIIA, PA, DSS, and SAB.

Method: 48 h post-fertilization zebrafish embryos were exposed either to each compound alone, TIIA (0.89 μg/mL), PA (0.41 μg/mL), DSS (0.59 μg/mL), SAB (2.15 μg/mL), and HSYA (1.83 μg/mL) and in combination with HSAY (1.83 μg/mL). The metabolites of TIIA, PA, DSS, SAB, and HSYA in zebrafish were characterized using high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) and quantitatively determined by HPLC-MS with single and combined exposure.

Results: Among the 26 metabolites detected and characterized from these five compounds, methylation, hydroxylation, dehydrogenation, hydrolysis, sulfation and glucuronidation were the main phase I and phase II metabolic reactions of these compounds, respectively. Furthermore, the results showed that HSYA could either enhance or reduce the amount of TIIA, PA, DSS, SAB, and their corresponding metabolites.

Conclusion: The results provided a reference for the study on drug interactions in vivo. In addition, the zebrafish model which required much fewer amounts of test samples, compared to regular mammal models, had higher efficiency in predicting in vivo metabolism of compounds.

Keywords: Tanshinone IIA, protocatechuic aldehyde, danshensu, salvianolic acid b, hydroxysafflor yellow, zebrafish, metabolism interaction.

Graphical Abstract
Liu, J.; Zhang, D.; Li, J.; Feng, J.; Yang, X.; Shi, D.; Liang, X. Effects of Salvia miltiorrhiza and Carthamus tinctorius aqueous extracts and compatibility on rat myocardial ischemic reperfusion injury Zhongguo Zhongyao Zazhi, 2011, 36(2), 189-194.
[PMID: 21506421]
Wang, X.P.; Bai, J.Q.; Hu, J.P.; Wang, J.; Wei, P.F.; Quan, L.N. Effect of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos before and after compatibility on activities of CYP1A2, CYP2E1, and CYP3A4 from rat liver microsomes. Yaowu Pingjia Yanjiu, 2017, 40(3), 300-306.
Wang, Y.L.; Hu, G.; Zhang, Q.; Yang, Y.X.; Li, Q.Q.; Hu, Y.J.; Chen, H.; Yang, F.Q. Screening and characterizing tyrosinase inhibitors from Salvia miltiorrhiza and Carthamus tinctorius by spectrum-effect relationship analysis and molecular docking. J. Anal. Methods Chem., 2018.20182141389
[] [PMID: 29862119]
Fan, H.J.; Yu, L.; Jin, W.F.; Li, M.; Zhou, J.; Li, X.H.; Zhang, Y.Y. Pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia. Zhongguo Zhongyao Zazhi, 2017, 42(13), 2564-2570.
[PMID: 28840700]
Hu, T.X.; Wen, A.D.; Zhu, Y.R.; Guan, Y. Protective effect of danshensu and hydrosafflor yellow A for using alone or in combination on myocardial ischemic-reperfusion injury in rats. Zhongguo Xiandai Zhongyao, 2015, 17(1), 15-19.
Liu, X.; Guo, C.Y.; Ma, X.J.; Wu, C.F.; Zhang, Y.; Sun, M.Y.; Pan, Y.T.; Yin, H.J. Anti-inflammatory effects of tanshinone IIA on atherosclerostic vessels of ovariectomized ApoE mice are mediated by estrogen receptor activation and through the ERK signaling pathway. Cell. Physiol. Biochem., 2015, 35(5), 1744-1755.
[] [PMID: 25832326]
Maione, F.; De Feo, V.; Caiazzo, E.; De Martino, L.; Cicala, C.; Mascolo, N. Tanshinone IIA, a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling pathway. J. Ethnopharmacol., 2014, 155(2), 1236-1242.
[] [PMID: 25038434]
Xuan, Y.; Gao, Y.; Huang, H.; Wang, X.; Cai, Y.; Luan, Q.X. Tanshinone IIA attenuates atherosclerosis in apolipoprotein E knockout mice Infected with Porphyromonas gingivalis. Inflammation, 2017, 40(5), 1631-1642.
[] [PMID: 28646427]
Yuan, X.; Jing, S.; Wu, L.; Chen, L.; Fang, J. Pharmacological postconditioning with tanshinone IIA attenuates myocardial ischemia-reperfusion injury in rats by activating the phosphatidylinositol 3-kinase pathway. Exp. Ther. Med., 2014, 8(3), 973-977.
[] [PMID: 25120632]
Li, P.; Wang, G.J.; Li, J.; Hao, H.P.; Zheng, C.N. Characterization of metabolites of tanshinone IIA in rats by liquid chromatography/tandem mass spectrometry. J. Mass Spectrom., 2006, 41(5), 670-684.
[] [PMID: 16598708]
Li, P.; Wang, G.J.; Li, J.; Hao, H.P.; Zheng, C.N. Identification of tanshinone IIA metabolites in rat liver microsomes by liquid chromatography-tandem mass spectrometry. J. Chromatogr. A, 2006, 1104(1-2), 366-369.
[] [PMID: 16405978]
Wei, Y.; Li, P.; Wang, C.; Peng, Y.; Shu, L.; Jia, X.; Ma, W.; Wang, B. Metabolism of tanshinone IIA, cryptotanshinone and tanshinone I from Radix Salvia miltiorrhiza in zebrafish. Molecules, 2012, 17(7), 8617-8632.
[] [PMID: 22810195]
Choi, J.; Jiang, X.; Jeong, J.B.; Lee, S.H. Anticancer activity of protocatechualdehyde in human breast cancer cells. J. Med. Food, 2014, 17(8), 842-848.
[] [PMID: 24712725]
Li, C.; Jiang, W.; Zhu, H.; Hou, J. Antifibrotic effects of protocatechuic aldehyde on experimental liver fibrosis. Pharm. Biol., 2012, 50(4), 413-419.
[] [PMID: 22129045]
Wei, G.; Guan, Y.; Yin, Y.; Duan, J.; Zhou, D.; Zhu, Y.; Quan, W.; Xi, M.; Wen, A. Anti-inflammatory effect of protocatechuic aldehyde on myocardial ischemia/reperfusion injury in vivo and in vitro. Inflammation, 2013, 36(3), 592-602.
[] [PMID: 23269534]
Zhao, X.; Zhai, S.Y.; An, M.S.; Wang, Y.H.; Yang, Y.F.; Ge, H.Q.; Liu, J.H.; Pu, X.P. Neuroprotective effects of protocatechuic aldehyde against neurotoxin-induced cellular and animal models of parkinson’s disease. PLoS One, 2013, 8(10)e78220
Zhang, S.; Yan, H.; Yu, P.; Xia, Y.; Zhang, W.; Liu, J. Development of protocatechualdehyde proliposomes-based sustained-release pellets with improved bioavailability and desired pharmacokinetic behavior for angina chronotherapy. Eur. J. Pharm. Sci., 2016, 93, 341-350.
[] [PMID: 27568854]
Xu, M.; Zhang, Z.; Fu, G.; Sun, S.; Sun, J.; Yang, M.; Liu, A.; Han, J.; Guo, D. Liquid chromatography-tandem mass spectrometry analysis of protocatechuic aldehyde and its phase I and II metabolites in rat. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2007, 856(1-2), 100-107.
[] [PMID: 17599847]
Tang, Y.; Wang, M.; Chen, C.; Le, X.; Sun, S.; Yin, Y. Cardiovascular protection with danshensu in spontaneously hypertensive rats. Biol. Pharm. Bull., 2011, 34(10), 1596-1601.
[] [PMID: 21963501]
Yin, Y.; Guan, Y.; Duan, J.; Wei, G.; Zhu, Y.; Quan, W.; Guo, C.; Zhou, D.; Wang, Y.; Xi, M.; Wen, A. Cardioprotective effect of Danshensu against myocardial ischemia/reperfusion injury and inhibits apoptosis of H9c2 cardiomyocytes via Akt and ERK1/2 phosphorylation. Eur. J. Pharmacol., 2013, 699(1-3), 219-226.
[] [PMID: 23200898]
Zhou, X.; Chan, S.W.; Tseng, H.L.; Deng, Y.; Hoi, P.M.; Choi, P.S.; Or, P.M.; Yang, J.M.; Lam, F.F.; Lee, S.M.; Leung, G.P.; Kong, S.K.; Ho, H.P.; Kwan, Y.W.; Yeung, J.H. Danshensu is the major marker for the antioxidant and vasorelaxation effects of Danshen (Salvia miltiorrhiza) water-extracts produced by different heat water-extractions. Phytomedicine, 2012, 19(14), 1263-1269.
[] [PMID: 23026310]
Gu, J.F.; Feng, L.; Zhang, M.H.; Qin, D.; Jiang, J.; Cheng, X.D.; Ding, S.M.; Yang, S.L.; Jia, X.B. New metabolite profiles of Danshensu in rats by ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2014, 955-956, 20-25.
[] [PMID: 24631806]
Wang, X.; Li, W.; Ma, X.; Yan, K.; Chu, Y.; Han, M.; Li, S.; Zhang, H.; Zhou, S.; Zhu, Y.; Sun, H.; Liu, C. Identification of a major metabolite of danshensu in rat urine and simultaneous determination of danshensu and its metabolite in plasma: application to a pharmacokinetic study in rats. Drug Test. Anal., 2015, 7(8), 727-736.
[] [PMID: 25557831]
Zhang, Z.C.; Xu, M.; Sun, S.F.; Qiao, X.; Wang, B.R.; Han, J.; Guo, D.A. Metabolic analysis of four phenolic acids in rat by liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2008, 871(1), 7-14.
[] [PMID: 18603488]
Han, D.; Wei, J.; Zhang, R.; Ma, W.; Shen, C.; Feng, Y.; Xia, N.; Xu, D.; Cai, D.; Li, Y.; Fang, W. Hydroxysafflor yellow A alleviates myocardial ischemia/reperfusion in hyperlipidemic animals through the suppression of TLR4 signaling. Sci. Rep., 2016, 6, 35319.
[] [PMID: 27731393]
Huber, G.A.; Priest, S.M.; Geisbuhler, T.P. Cardioprotective effect of hydroxysafflor yellow A via the cardiac permeability transition pore. Planta Med., 2018, 84(8), 507-518.
[] [PMID: 29165728]
Jiang, B.; Chen, J.; Xu, L.; Gao, Z.; Deng, Y.; Wang, Y.; Xu, F.; Shen, X.; Guo, D.A. Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling. BMC Pharmacol., 2010, 10, 10.
[] [PMID: 20735854]
Jing, Z.; Fei, W.; Zhou, J.; Zhang, L.; Chen, L.; Zhang, X.; Liang, X.; Xie, J.; Fang, Y.; Sui, X.; Han, W.; Pan, H. Salvianolic acid B, a novel autophagy inducer, exerts antitumor activity as a single agent in colorectal cancer cells. Oncotarget, 2016, 7(38), 61509-61519.
[] [PMID: 27557491]
Wang, S.X.; Hu, L.M.; Gao, X.M.; Guo, H.; Fan, G.W. Anti-inflammatory activity of salvianolic acid B in microglia contributes to its neuroprotective effect. Neurochem. Res., 2010, 35(7), 1029-1037.
[] [PMID: 20238162]
Wei, G.; Yin, Y.; Duan, J.; Guo, C.; Zhu, Y.; Wang, Y.; Xi, M.; Wen, A. Hydroxysafflor yellow A promotes neovascularization and cardiac function recovery through HO-1/VEGF-A/SDF-1α cascade. Biomed. Pharmacother., 2017, 88, 409-420.
[] [PMID: 28122306]
Xi, S.Y.; Zhang, Q.; Liu, C.Y.; Xie, H.; Yue, L.F.; Gao, X.M. Effects of hydroxy safflower yellow-A on tumor capillary angiogenesis in transplanted human gastric adenocarcinoma BGC-823 tumors in nude mice. J. Tradit. Chin. Med., 2012, 32(2), 243-248.
[] [PMID: 22876451]
Yu, J.; Chen, R.; Tan, Y.; Wu, J.; Qi, J.; Zhang, M.; Gu, W. Salvianolic acid B alleviates heart failure by inactivating ERK1/2/GATA4 signaling pathway after pressure overload in mice. PLoS One, 2016, 11(11)e0166560
[] [PMID: 27893819]
Jin, Y.; Wu, L.; Tang, Y.; Cao, Y.; Li, S.; Shen, J.; Yue, S.; Qu, C.; Shan, C.; Cui, X.; Zhang, L.; Duan, J.A. UFLC-Q-TOF/MS based screening and identification of the metabolites in plasma, bile, urine and feces of normal and blood stasis rats after oral administration of hydroxysafflor yellow A. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2016, 1012-1013, 124-129.
[] [PMID: 26827279]
Miao, J.; Sun, W.; Huang, J.; Liu, X.; Li, S.; Han, X.; Tong, L.; Sun, G. Characterization of metabolites in rats after intravenous administration of salvianolic acid for injection by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Biomed. Chromatogr., 2016, 30(9), 1487-1497.
[] [PMID: 26910272]
Qi, Q.; Hao, K.; Li, F.Y.; Cao, L.J.; Wang, G.J.; Hao, H.P. The identification and pharmacokinetic studies of metabolites of salvianolic acid B after intravenous administration in rats. Chin. J. Nat. Med., 2013, 11(5), 560-565.
[] [PMID: 24359784]
Wu, L.; Tang, Y.; Shan, C.; Chai, C.; Zhou, Z.; Shi, X.; Ding, N.; Wang, J.; Lin, L.; Tan, R. A comprehensive in vitro and in vivo metabolism study of hydroxysafflor yellow A. J. Mass Spectrom., 2018, 53(2), 99-108.
[] [PMID: 29076598]
Goldsmith, P. Zebrafish as a pharmacological tool: the how, why and when. Curr. Opin. Pharmacol., 2004, 4(5), 504-512.
[] [PMID: 15351356]
Liang, A. Zebrafish--useful model for pharmacodynamics and toxicity screening of traditional Chinese medicine Zhongguo Zhongyao Zazhi, 2009, 34(22), 2839-2842.
[PMID: 20209941]
Kari, G.; Rodeck, U.; Dicker, A.P. Zebrafish: an emerging model system for human disease and drug discovery. Clin. Pharmacol. Ther., 2007, 82(1), 70-80.
[] [PMID: 17495877]
Jones, H.S.; Trollope, H.T.; Hutchinson, T.H.; Panter, G.H.; Chipman, J.K. Metabolism of ibuprofen in zebrafish larvae. Xenobiotica, 2012, 42(11), 1069-1075.
[] [PMID: 22594345]
Wei, Y.J.; Ning, Q.; Jia, X.B.; Gong, Z.N. Thoughts and methods for metabolic study of Chinese materia medica based on zebrafish model. Chin. Tradit. Herbal Drugs, 2009, 40(7), 1009-1011.
Wei, Y.; Li, P.; Fan, H.; Sun, E.; Wang, C.; Shu, L.; Liu, W.; Xue, X.; Qian, Q.; Jia, X. Metabolite profiling of four major flavonoids of Herba Epimedii in zebrafish. Molecules, 2012, 17(1), 420-432.
[] [PMID: 22217555]
Hu, G.; Siu, S.O.; Li, S.; Chu, I.K.; Kwan, Y.W.; Chan, S.W.; Leung, G.P.; Yan, R.; Lee, S.M. Metabolism of calycosin, an isoflavone from Astragali Radix, in zebrafish larvae. Xenobiotica, 2012, 42(3), 294-303.
[] [PMID: 21961561]
Ibhazehiebo, K.; Gavrilovici, C.; de la Hoz, C.L. A novel metabolism-based phenotypic drug discovery platform in zebrafish uncovers hdacs 1 and 3 as a potential combined anti-seizure drug target. Brain, 2018.
de Souza Anselmo, C.; Sardela, V.F.; Matias, B.F.; de Carvalho, A.R.; de Sousa, V.P.; Pereira, H.M.G.; de Aquino Neto, F.R. Is zebrafish (Danio rerio) a tool for human-like metabolism study? Drug Test. Anal., 2017, 9(11-12), 1685-1694.
[] [PMID: 28987069]
Sun, J.; Yang, M.; Han, J.; Wang, B.; Ma, X.; Xu, M.; Liu, P.; Guo, D. Profiling the metabolic difference of seven tanshinones using high-performance liquid chromatography/multi-stage mass spectrometry with data-dependent acquisition. Rapid Commun. Mass Spectrom., 2007, 21(14), 2211-2226.
[] [PMID: 17569103]
Zeng, G.; Xiao, H.; Liu, J.; Liang, X. Identification of phenolic constituents in Radix Salvia miltiorrhizae by liquid chromatography/electrospray ionization mass spectrometry. Rapid Commun. Mass Spectrom., 2006, 20(3), 499-506.
[] [PMID: 16402343]
Xu, M.; Guo, H.; Han, J.; Sun, S.F.; Liu, A.H.; Wang, B.R.; Ma, X.C.; Liu, P.; Qiao, X.; Zhang, Z.C.; Guo, D.A. Structural characterization of metabolites of salvianolic acid B from Salvia miltiorrhiza in normal and antibiotic-treated rats by liquid chromatography-mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2007, 858(1-2), 184-198.
[] [PMID: 17875406]
Wei, Y.J.; Jia, X.B.; Zhan, Y.; Wang, C.M.; Ma, W.Q.; Wang, B.; Xu, L.L. I metabolic study on combination of tanshinone IIA, cryptotanshinone, and tanshinone I in zebrafish. Chin. Tradit. Herbal Drugs, 2013, 44(9), 1149-1156.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy