Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

Qiu, Furong; Zhang, Rong; Sun, Jianguo; Aa, Jiye; Hao, Haiping; Peng, Ying; Ai, Hua; Wang, Guangji

doi:10.1124/dmd.108.021030

Cited by 97 publications

(68 citation statements)

References 25 publications

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“…The measured values were in good agreement with recently published literatures (21,(24)(25)(26)(27)(28), demonstrating applicability of the assay. Therefore, PHE/OME/TOL/DEX/MID/TES at 20/10/40/6/2/40 μM were chosen as probe substrates to evaluate candidate compounds for their inhibition of CYP1A2, 2C9, 2C19, 2D6, and 3A4/5 (MID and TES), respectively.…”

Section: Optimization and Verification Of The Incubation Systemsupporting

confidence: 80%

“…3S. Most of these potent inhibitors (23,28,(30)(31)(32)38) contained an isoprenyl group, which was very close to the heme region of CYP1A2, and could contribute to their inhibitory activities (ESM Fig. 3S).…”

Section: P450 Inhibition Assay For 40 Licorice Compoundsmentioning

confidence: 99%

“…Chemical structures of licorice compounds (isolated from Glycyrrhiza uralensis Fisch.). The compounds were 4-hydroxybenzoic acid (1), phloretic acid (2), liquiritin apioside (3), liquiritin (4), isoliquiritin apioside (5), isoliquiritin (6), ononin (7), 4′,7-dihydroxyflavone (8), liquiritigenin (9), licoricesaponin A3 (10), licopyranocoumarin (11), echinatin (12), naringenin (13), genistein (14), licorice-saponin G2 (15), licorice-saponin E2 (16), 3-methylkaempferol (17), davidigenin (18), glycyrrhizic acid (19), isoliquiritigenin (20), 7,4′-dihydroxy-3′-methoxyisoflavan (21), formononetin (22), glycycoumarin (23), semilicoisoflavone B (24), kumatakenin (25), licoisoflavone A (26), licoricone (27), isolicoflavonol (28), lupiwighteone (29), glycyrol (30), glyurallin A (31), licoflavonol (32), topazolin (33), glycyrin (34), gancaonin I (35), angustone A (36), isoangustone A (37), gancaonin G (38), 6,8-diprenylgenistein (39), and 18β-glycyrrhetinic acid (40). Api apinose, GluA glucuronic acid, Glc glucose, Prenyl isoprenoid.…”

Section: Lc/ms/ms Assaymentioning

confidence: 99%

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Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/MS/MS Cocktail Assay and Metabolic Profiling

Qiao

et al. 2013

AAPS J

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Abstract. Licorice has been shown to affect the activities of several cytochrome P450 enzymes. This study aims to identify the key constituents in licorice which may affect these activities. Bioactivity assay was combined with metabolic profiling to identify these compounds in several complex licorice extracts. Firstly, the inhibition potencies of 40 pure licorice compounds were tested using an liquid chromatography/tandem mass spectrometry cocktail method. Significant inhibitors of human P450 isozymes 1A2, 2C9, 2C19, 2D6, and 3A4 were then selected for examination of their structural features by molecular docking to determine their molecular interaction with several P450 isozymes. Based on the present in vitro inhibition findings, along with our previous in vivo metabolic studies and the prevalence of individual compounds in licorice extract, we identified several licorice constituents, viz., liquiritigenin, isoliquiritigenin, together with seven isoprenylated flavonoids and arylcoumarins, which could be key components responsible for the herb-drug interaction between cytochrome P450 and licorice. In addition, hydrophilic flavonoid glycosides and saponins may be converted into these P450 inhibitors in vivo. These studies represent a comprehensive examination of the potential effects of licorice components on the metabolic activities of P450 enzymes.

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Section: Optimization and Verification Of The Incubation Systemsupporting

confidence: 80%

Section: P450 Inhibition Assay For 40 Licorice Compoundsmentioning

confidence: 99%

Section: Lc/ms/ms Assaymentioning

confidence: 99%

See 1 more Smart Citation

Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/MS/MS Cocktail Assay and Metabolic Profiling

Qiao

et al. 2013

AAPS J

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“…The reaction was terminated by addition of cold acetonitrile. After centrifugation, the supernatant was injected into a HPLC or liquid chromatography mass spectrometry system (Shimadzu) for analysis, as described previously (Lofgren et al, 2004;Qiu et al, 2008). All incubations were performed in triplicates.…”

Section: Methodsmentioning

confidence: 99%

Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor α–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes

et al. 2015

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Silybin, a major pharmacologically active compound in silymarin, has been widely used in combination with other prescriptions in the clinic to treat hepatitis and a host of other diseases. Previous studies suggested that silybin is a potential inhibitor of multiple drug-metabolizing enzymes (DMEs); however, the in vitro to in vivo translation and the mechanisms involved remain established. The aim of this study was to provide a mechanistic understanding of the regulatory effects of silybin on principal DMEs. Silybin (50 or 150 mg/kg/d) was administered to mice for a consecutive 14 days. The plasma and hepatic exposure of silybin were detected; the mRNA, protein levels, and enzyme activities of principal DMEs were determined. The results demonstrated that the enzyme activities of CYP1A2, CYP2C, CYP3A11, and UGT1A1 were significantly repressed, whereas little alteration of the mRNA and protein levels was observed. Silybin inhibits these DMEs in a mechanism-based and/or substrate-competitive manner. More importantly, silybin was found to be a weak agonist of peroxisome proliferator-activated receptor (PPAR)a, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPARa by fenofibrate, characterized with significantly repressed expression of PPARa targeting genes, including L-FABP, ACOX1, and UGT1A6. This study suggests that silybin, despite its low bioavailability, may inhibit enzyme activities of multiple DMEs in a mechanism-based mode, and more importantly, may confer significant drug-drug interaction with PPARa agonists via the repression of PPARa activation in a competitive mode.

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“…The study design was a sequential, openlabel, two-period trial [13] conducted at the Drug Clinical Research Organization of Yijishan Hospital. On the morning of day 1, after fasting overnight, a single dose of 15 mg midazolam was administered orally.…”

Section: Methodsmentioning

confidence: 99%

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

Qiu

Wang

Zhang

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many cytochrome P450 mediated interactions have been reported between drug and herbal medicines. In particular, CYP3A4 is known to play a critical role in several clinically relevant herb-drug interactions. Midazolam has been reported to be one of the preferred in vivo CYP3A probes.• It has been reported that the lipophilic components of danshen could induce CYP3A in C57BL/6J mice, that cryptotanshinone and tanshinone IIA of danshen extract could activate human PXR and consequently induce the expression of the CYP3A4 gene. WHAT THIS STUDY ADDS• Co-administration of multiple doses of danshen tablets caused an increase in apparent oral clearance of midazolam by 35.4%, a corresponding decline in Cmax by 31.1% and a decline in AUC(0,•) by 27.0% in human volunteers. The t1/2 of midazolam and 1-hydroxymidazolam were not changed, and the Cmax and AUC(0,•) ratio of midazolam to 1-hydroxymidazolam were not affected. The results suggested that multiple dose administration of danshen tablets could induce CYP3A4 in the gut, thereby increasing the clearance of midazolam. Therefore, caution should be taken when danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A. AIMSTo assess the effect of danshen extract on CYP3A4 activity using midazolam as an in vivo probe. METHODSA sequential, open-label, two-period pharmacokinetic interaction study design was used to compare midazolam pharmacokinetic parameters before and after 14 days of administration of danshen tablets. Twelve healthy volunteers received a single oral dose (15 mg) of midazolam followed by danshen tablets (four tablets orally, three times a day) for 14 days. On the last day of the study they received four danshen tablets with a 15 mg midazolam tablet and plasma concentrations of midazolam and its corresponding metabolite 1-hydroxylmidazolam were measured prior to and after the administration of danshen tablets periodically for 12 h. RESULTSThe 90% confidence intervals of Cmax, t1/2, CL/F and AUC(0,•) of midazolam before and after administration of danshen tablets were (0.559, 0.849), (0.908, 1.142), (1.086, 1.688) and (0.592, 0.921), respectively; and those of Cmax, t1/2 and AUC(0,•) of 1-hydroxylmidazolam after vs. before administration of danshen tablets were (0.633, 0.923), (0.801, 1.210) and (0.573, 0.980), respectively. Ratios of geometric LS means of Cmax(1OHMid) : Cmax(Mid) and AUCmax(1OHMid) : AUCmax(Mid) (after vs. before 14-day danshen) were 1.072 and 1.035, respectively. CONCLUSIONSOur findings suggest that multiple dose administration of danshen tablets may induce CYP3A4 in the gut. Accordingly, caution should be taken when danshen products are used in combination with therapeutic drugs metabolized by CYP3A. Danshen, the dried root of Salvia miltiorrhiza, has been used for more than 2000 years in China for the treatment of numerous ailments [6]. Danshen extract contains both hydrophilic components (danshensu, protocatechuic aldehyde and salvianolic a...

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Inhibitory Effects of Seven Components of Danshen Extract on Catalytic Activity of Cytochrome P450 Enzyme in Human Liver Microsomes

Cited by 97 publications

References 25 publications

Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/MS/MS Cocktail Assay and Metabolic Profiling

Identification of Key Licorice Constituents Which Interact with Cytochrome P450: Evaluation by LC/MS/MS Cocktail Assay and Metabolic Profiling

Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor α–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

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