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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

Comparison of Sweated and Non-Sweated Ethanol Extracts of Salvia miltiorrhiza Bge. (Danshen) Effects on Human and Rat Hepatic UDP-Glucuronosyltransferase and Preclinic Herb-Drug Interaction Potential Evaluation

Author(s): Jie Liu, Yun Shi, Chengyuan Wu, Bangzhen Hong, Daiyin Peng, Nianjun Yu, Guokai Wang, Lei Wang and Weidong Chen*

Volume 23, Issue 6, 2022

Published on: 13 July, 2022

Page: [473 - 483] Pages: 11

DOI: 10.2174/1389200223666220517115845

Price: $65

Abstract

Background: The ethanol of Danshen (DEE) preparation has been widely used to treat cardiac-cerebral disease and cancer. Sweating is one of the primary processing methods of Danshen, which greatly influences its quality and pharmacological properties. Sweated and non-sweated DEE preparation combined with various synthetic drugs, add up the possibility of herbal-drug interactions.

Objective: This study explored the effects of sweated and non-sweated DEE on human and rat hepatic UGT enzyme expression and activity and proposed a potential mechanism.

Methods: The expression of two processed DEE on rat UGT1A, UGT2B, and nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor α (PPARα), were investigated after intragastric administration in rats by Western blot. Enzyme activity of DEE and its active ingredients (Tanshinone I, Cryptotanshinone, and Tanshinone I) on UGT isoenzymes was evaluated by quantifying probe substrate metabolism and metabolite formation in vitro using Ultra Performance Liquid Chromatography.

Results: The two processed DEE (5.40 g/kg) improved UGT1A (P<0.01) and UGT2B (P<0.05) protein expression, and the non-sweated DEE (2.70 g/kg) upregulated UGT2B expression protein (P<0.05), compared with the CMCNa group. On day 28, UGT1A protein expression was increased (P<0.05) both in two processed DEE groups meanwhile, the non-sweated DEE significantly enhanced UGT2B protein expression (P<0.05) on day 21, compared with the CMCNa group. The process underlying this mechanism involved the activation of nuclear receptors CAR, PXR, and PPARα. In vitro, sweated DEE (0-80 μg/mL) significantly inhibited the activity of human UGT1A7 (P<0.05) and rat UGT1A1, 1A8, and 1A9 (P<0.05). Non-sweated DEE (0-80 μg/mL) dramatically suppressed the activity of human UGT1A1, 1A3, 1A6, 1A7, 2B4, and 2B15, and rat UGT1A1, 1A3, 1A7, and 1A9 (P<0.05). Tanshinone I (0-1 μM) inhibited the activity of human UGT1A3, 1A6, and 1A7 (P<0.01) and rat UGT1A3, 1A6, 1A7, and 1A8 (P<0.05). Cryptotanshinone (0-1 μM) remarkably inhibited the activity of human UGT1A3 and 1A7 (P<0.05) and rat UGT1A7, 1A8, and 1A9 (P<0.05). Nonetheless, Tanshinone IIA (0-2 μM) is not a potent UGT inhibitor both in humans and rats. Additionally, there existed significant differences between two processed DEE in the expression of PXR, and the activity of human UGT1A1, 1A3, 1A6, and 2B15 and rat UGT1A3, and 2B15 (P<0.05).

Conclusion: The effects of two processed DEE on hepatic UGT enzyme expression and activity differed. Accordingly, the combined usage of related UGTs substrates with DEE and its monomer components preparations may call for caution, depending on the drug’s exposure-response relationship and dose adjustment. Besides, it is vital to pay attention to the distinction between sweated and non-sweated Danshen in clinic, which influences its pharmacological activity.

Keywords: Ethanol extract of Danshen, UGT, sweated, non-sweated, CAR, PXR, PPARα.

Graphical Abstract

[1]
Nair, P.C.; Meech, R.; Mackenzie, P.I.; McKinnon, R.A.; Miners, J.O. Insights into the UDP-sugar selectivities of human UDP-glycosyltransferases (UGT): A molecular modeling perspective. Drug Metab. Rev., 2015, 47(3), 335-345.
[PMID: 26289097]
[2]
Kiang, T.K.; Ensom, M.H.; Chang, T.K. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol. Ther., 2005, 106(1), 97-132.
[http://dx.doi.org/10.1016/j.pharmthera.2004.10.013] [PMID: 15781124]
[3]
Kostrubsky, S.E.; Sinclair, J.F.; Strom, S.C.; Wood, S.; Urda, E.; Stolz, D.B.; Wen, Y.H.; Kulkarni, S.; Mutlib, A. Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol. Sci., 2005, 87(1), 146-155.
[http://dx.doi.org/10.1093/toxsci/kfi211] [PMID: 15933229]
[4]
Deng, C.; Deng, B.; Jia, L.; Tan, H.; Zhang, P.; Liu, S.; Zhang, Y.; Song, A.; Pan, L. Preventive effects of a Chinese herbal formula, shengjiang xiexin decoction, on irinotecan-induced delayed-onset diarrhea in rats. Evid. Based Complement. Alternat. Med., 2017, 2017, 7350251.
[http://dx.doi.org/10.1155/2017/7350251] [PMID: 28167974]
[5]
Li, Z.M.; Xu, S.W.; Liu, P.Q. Salvia miltiorrhiza burge (Danshen): A golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol. Sin., 2018, 39(5), 802-824.
[http://dx.doi.org/10.1038/aps.2017.193] [PMID: 29698387]
[6]
Zhou, X.; Chan, K.; Yeung, J.H. Herb-drug interactions with Danshen (Salvia miltiorrhiza): A review on the role of cytochrome P450 enzymes. Drug Metabol. Drug Interact., 2012, 27(1), 9-18.
[http://dx.doi.org/10.1515/dmdi-2011-0038] [PMID: 22718621]
[7]
Wu, W.W.; Yeung, J.H. Inhibition of warfarin hydroxylation by major tanshinones of Danshen (Salvia miltiorrhiza) in the rat in vitro and in vivo. Phytomedicine, 2010, 17(3-4), 219-226.
[http://dx.doi.org/10.1016/j.phymed.2009.05.005] [PMID: 19577456]
[8]
Zhou, C.H.; Xu, M.; Yu, H.B.; Zheng, X.T.; Zhong, Z.F.; Zhang, L.T. Effects of Danshen capsules on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. Food Chem. Toxicol., 2018, 119, 302-308.
[http://dx.doi.org/10.1016/j.fct.2018.02.051] [PMID: 29496531]
[9]
Zhang, X.X.; Cao, Y.F.; Wang, L.X.; Yuan, X.L.; Fang, Z.Z. Inhibitory effects of tanshinones towards the catalytic activity of UDP-glucuronosyltransferases (UGTs). Pharm. Biol., 2017, 55(1), 1703-1709.
[http://dx.doi.org/10.3109/13880209.2015.1045621] [PMID: 28466663]
[10]
Guo, L.; Duan, L.; Dong, X.; Dou, L.L.; Zhou, P.; Li, P.; Liu, E.H. Metabolic profile of miltirone in rats by high performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J. Pharm. Biomed. Anal., 2015, 107, 473-479.
[http://dx.doi.org/10.1016/j.jpba.2015.01.043] [PMID: 25679091]
[11]
Cao, M.; Liu, Y.; Jiang, W.; Meng, X.; Zhang, W.; Chen, W.; Peng, D.; Xing, S. UPLC/MS-based untargeted metabolomics reveals the changes of metabolites profile of Salvia miltiorrhiza bunge during Sweating processing. Sci. Rep., 2020, 10(1), 19524.
[http://dx.doi.org/10.1038/s41598-020-76650-w] [PMID: 33177654]
[12]
Li, G.; Yu, F.; Wang, Y.; Yao, L.; Qiu, Z.; Wang, T.; Wang, Z.; Yang, F.; Peng, D.; Yu, N.; Chen, W. Comparison of the chromatographic fingerprint, multicomponent quantitation and antioxidant activity of Salvia miltiorrhiza Bge. between sweating and nonsweating. Biomed. Chromatogr., 2018, 32(6), e4203.
[http://dx.doi.org/10.1002/bmc.4203] [PMID: 29399849]
[13]
Liu, J.; Shan, X.X.; Li, G.Z. Rapid identification of Salvia miltiorrhiza under different sweating environments by infrared spectroscopy combined with chemometrics. J. Anhui Univ. Tradit. Chin. Med., 2021, 40, 85-90.
[14]
Li, G.Z. Study of the effects of sweated and none sweated Salvia miltiorrhiza Bge. on the cytochrome P450 enzyme in rats. Dissertation. Anhui University of Chinese Medicine, 2018.
[15]
Li, G.Z.; Peng, D.Y.; Chen, W.D. Optimization of extraction technology for tanshnones by orthogonal test design combining HPLC fingerprint. Jiangxi Zhongyiyao Daxue Xuebao, 2017, 29, 67-70.
[16]
Miners, J.O.; Lillywhite, K.J.; Matthews, A.P.; Jones, M.E.; Birkett, D.J. Kinetic and inhibitor studies of 4-methylumbelliferone and 1-naphthol glucuronidation in human liver microsomes. Biochem. Pharmacol., 1988, 37(4), 665-671.
[http://dx.doi.org/10.1016/0006-2952(88)90140-2] [PMID: 3124857]
[17]
Kolrep, F.; Rein, K.; Lampen, A.; Hessel-Pras, S. Metabolism of okadaic acid by NADPH-dependent enzymes present in human or rat liver S9 fractions results in different toxic effects. Toxicol. In Vitro, 2017, 42, 161-170.
[http://dx.doi.org/10.1016/j.tiv.2017.04.009] [PMID: 28414161]
[18]
Zhou, J.; Tracy, T.S.; Remmel, R.P. Glucuronidation of dihydrotestosterone and trans-androsterone by recombinant UDP-glucuronosyl-transferase (UGT) 1A4: Evidence for multiple UGT1A4 aglycone binding sites. Drug Metab. Dispos., 2010, 38(3), 431-440.
[http://dx.doi.org/10.1124/dmd.109.028712] [PMID: 20007295]
[19]
Wang, X.; Yeung, J.H. Effects of Salvia miltiorrhiza extract on the liver CYP3A activity in humans and rats. Phytother. Res., 2011, 25(11), 1653-1659.
[http://dx.doi.org/10.1002/ptr.3472] [PMID: 21425376]
[20]
Uchaipichat, V.; Mackenzie, P.I.; Guo, X.H.; Gardner-Stephen, D.; Galetin, A.; Houston, J.B.; Miners, J.O. Human UDP-glucuronosyltransferases: Isoform selectivity and kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents, and inhibition by diclofenac and probenecid. Drug Metab. Dispos., 2004, 32(4), 413-423.
[http://dx.doi.org/10.1124/dmd.32.4.413] [PMID: 15039294]
[21]
Uchaipichat, V.; Mackenzie, P.I.; Elliot, D.J.; Miners, J.O. Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) “probes” for human udp-glucuronosyltransferases. Drug Metab. Dispos., 2006, 34(3), 449-456.
[http://dx.doi.org/10.1124/dmd.105.007369] [PMID: 16381668]
[22]
Liu, Y.; Ramírez, J.; House, L.; Ratain, M.J. Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab. Dispos., 2010, 38(1), 32-39.
[http://dx.doi.org/10.1124/dmd.109.029660] [PMID: 19850672]
[23]
Mackenzie, P.I.; Hu, D.G.; Gardner-Stephen, D.A. The regulation of UDP-glucuronosyltransferase genes by tissue-specific and ligand-activated transcription factors. Drug Metab. Rev., 2010, 42(1), 99-109.
[http://dx.doi.org/10.3109/03602530903209544] [PMID: 20070244]
[24]
Wang, T. Study of the effects of sweated and none sweated Salvia miltiorrhiza Bge. on the cytochrome P450 enzyme in HepG2 cells by nuclear receptor PXR and CAR; Dissertation.. Anhui University of Chinese Medicine, 2020.
[25]
Yu, C.; Ye, S.; Sun, H. PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA. Chem. Biol. Interact., 2009, 177(1), 58-64.
[26]
Ding, L.; Wo, L.; Du, Z.; Tang, L.; Song, Z.; Dou, X. Danshen protects against early-stage alcoholic liver disease in mice via inducing PPARα activation and subsequent 4-HNE degradation. PLoS One, 2017, 12(10), e0186357.
[http://dx.doi.org/10.1371/journal.pone.0186357] [PMID: 29020055]
[27]
Shelby, M.K.; Klaassen, C.D. Induction of rat UDP-glucuronosyltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways. Drug Metab. Dispos., 2006, 34(10), 1772-1778.
[http://dx.doi.org/10.1124/dmd.106.010397] [PMID: 16855052]
[28]
Wang, X.; Yeung, J.H. Investigation of cytochrome P450 1A2 and 3A inhibitory properties of Danshen tincture. Phytomedicine, 2012, 19(3-4), 348-354.
[http://dx.doi.org/10.1016/j.phymed.2011.09.075] [PMID: 22056022]
[29]
Li, Y.; Fan, Y.; Su, H.; Wang, Q.; Li, G.F.; Hu, Y.; Jiang, J.; Tan, B.; Qiu, F. Metabolic characteristics of Tanshinone I in human liver microsomes and S9 subcellular fractions. Xenobiotica, 2019, 49(2), 152-160.
[http://dx.doi.org/10.1080/00498254.2018.1432087] [PMID: 29357726]
[30]
Zeng, J.; Fan, Y.J.; Tan, B.; Su, H.Z.; Li, Y.; Zhang, L.L.; Jiang, J.; Qiu, F.R. Charactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro. Acta Pharmacol. Sin., 2018, 39(8), 1393-1404.
[http://dx.doi.org/10.1038/aps.2017.144] [PMID: 29417949]
[31]
Cong, M.; Hu, C.M.; Cao, Y.F.; Fang, Z.Z.; Tang, S.H.; Wang, J.R.; Luo, J.S. Cryptotanshinone and dihydrotanshinone I exhibit strong inhibition towards human liver microsome (HLM)-catalyzed propofol glucuronidation. Fitoterapia, 2013, 85, 109-113.
[http://dx.doi.org/10.1016/j.fitote.2013.01.002] [PMID: 23333907]
[32]
Ueng, Y.F.; Kuo, Y.H.; Wang, S.Y.; Lin, Y.L.; Chen, C.F. Induction of CYP1A by a diterpene quinone tanshinone IIA isolated from a medicinal herb Salvia miltiorrhiza in C57BL/6J but not in DBA/2J mice. Life Sci., 2004, 74(7), 885-896.
[http://dx.doi.org/10.1016/j.lfs.2003.07.035] [PMID: 14659977]
[33]
Wang, Q.; Hao, H.; Zhu, X.; Yu, G.; Lai, L.; Liu, Y.; Wang, Y.; Jiang, S.; Wang, G. Regioselective glucuronidation of tanshinone IIa after quinone reduction: Identification of human UDP-glucuronosyl-transferases, species differences, and interaction potential. Drug Metab. Dispos., 2010, 38(7), 1132-1140.
[http://dx.doi.org/10.1124/dmd.109.031864] [PMID: 20382756]
[34]
Rad, G.; Hoehle, S.I.; Kuester, R.K.; Sipes, I.G. In vitro glucuronidation of 2,2-bis(bromomethyl)-1,3-propanediol by microsomes and hepatocytes from rats and humans. Drug Metab. Dispos., 2010, 38(6), 957-962.
[http://dx.doi.org/10.1124/dmd.110.032110] [PMID: 20200232]
[35]
Sun, H.; Zhang, T.; Wu, Z.; Wu, B. Warfarin is an effective modifier of multiple UDP-glucuronosyltransferase enzymes: Evaluation of its potential to alter the pharmacokinetics of zidovudine. J. Pharm. Sci., 2015, 104(1), 244-256.
[http://dx.doi.org/10.1002/jps.24250] [PMID: 25393417]
[36]
Yang, J.; Hasegawa, J.; Endo, Y.; Iitsuka, K.; Yamamoto, M.; Matsuda, A. Pharmacokinetic drug interaction between rosuvastatin and tanjin in healthy volunteers and rats. Yonago Acta Med., 2019, 62(1), 77-84.
[http://dx.doi.org/10.33160/yam.2019.03.011] [PMID: 30962748]
[37]
Schirris, T.J.; Ritschel, T.; Bilos, A.; Smeitink, J.A.; Russel, F.G. Statin Lactonization by Uridine 5′-Diphospho-glucuronosyl-transferases (UGTs). Mol. Pharm., 2015, 12(11), 4048-4055.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00474] [PMID: 26412035]
[38]
Prueksaritanont, T.; Tang, C.; Qiu, Y.; Mu, L.; Subramanian, R.; Lin, J.H. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos., 2002, 30(11), 1280-1287.
[http://dx.doi.org/10.1124/dmd.30.11.1280] [PMID: 12386136]
[39]
Prueksaritanont, T.; Zhao, J.J.; Ma, B.; Roadcap, B.A.; Tang, C.; Qiu, Y.; Liu, L.; Lin, J.H.; Pearson, P.G.; Baillie, T.A. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther., 2002, 301(3), 1042-1051.
[http://dx.doi.org/10.1124/jpet.301.3.1042] [PMID: 12023536]
[40]
Wang, T.; Yu, F.; Li, G.Z. Content determination of ten active components in Salvia miltiorrhiza with or without sweating treatment and quality evaluation based on a principal component analysis. J. Anhui Univ. Tradit. Chin. Med., 2019, 38, 75-79.
[41]
Zheng, Y.L.; Wang, X.; Liu, F. Exploration of scientific connotation of Magnoliae officinalis Cortex after sweating based on network pharmacology. J. Chin. Herb. Med., 2019, 50, 1857-1862.

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