PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA

Yu, Chunna; Ye, Shanshan; Sun, Hongying; Liu, Yao; Gao, Lingbo; Shen, Chaofeng; Chen, Shuqing; Zeng, Su

doi:10.1016/j.cbi.2008.08.013

Cited by 61 publications

(42 citation statements)

References 33 publications

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“…Additionally, the PXR-and CAR-dependent induction of CYP3A4 is enhanced by GR [25,26]. Compared with CYP3A4, CYP3A5 may be a relatively minor enzyme in the human small bowel, and appears to be less sensitive to induction by PXR activators because it lacks the distal PXRresponse element cluster shown to enhance the transcription of CYP3A4 by xenobiotics [27,28].Yu et al [12] found that tanshinone IIA and cryptotanshinone were efficacious activators for human PXR, GR was also involved in the trans-activation of the CYP3A4 promoter by cryptotanshinone and tanshinone IIA, and CAR played a role in tanshinone IIA-mediated CYP3A4 induction. The in vitro study results reported are consistent with our in vivo findings here.…”

Section: Discussionmentioning

confidence: 99%

“…Kuo et al reported that the ethyl acetate extract (lipophilic components) of danshen could induce expression of CYP3A in C57BL/6J mice [11]. Using the reporter gene assay and polymerase chain reaction (PCR) Yu et al [12] found that tanshinone IIA and cryptotanshinone were efficacious pregnant X receptor (PXR) agonists, and that constitutive androstane receptor(CAR) and glucocorticoid receptor (GR) were, to a lesser extent, involved in the induction of CYP3A4 expression by tanshinones.Yu's group also found that treatment of LS174T cells with cryptotanshinone or tanshinone IIA resulted in a significant increase of CYP3A4 mRNA and concluded that activation of PXR and the resultant CYP3A4 induction was mediated by cryptotanshinone and tanshinone IIA. Our previous findings indicated that seven (three lipophilic and four hydrophilic) components of danshen extract had no inhibitory effect on CYP3A4 enzyme activity in liver microsomes [13].…”

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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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Section: Discussionmentioning

confidence: 99%

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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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“…Dimethyl sulfoxide (DMSO), MTT and non-essential amino acids were obtained from Sigma-Aldrich (St. Louis, MO, USA). The plasmids, pcDNA3.1-hPXR, pGL3-PXRE and pRL-TK, were constructed as previously described (19). Mega Tran 1.0 transfection reagent was purchased from OriGene (Rockville, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Reporter gene assays were performed as described previously (19) with a slight modification. Briefly, plasmid DNA was prepared by the E.Z.N.A.™Endo-free Plasmid Mini kit.…”

Section: Methodsmentioning

confidence: 99%

“…The PXR-CYP3A4 pathway has been clarified as a common mechanism mediating the HDIs. For instance, St. John's wort was found to induce CYP3A4 expression through activation of the PXR (18) and cryptotanshinone and tanshinone IIA, the major bioactive components from Danshen herb, were identified as efficacious PXR agonists and induced CYP3A4 expression via the PXR-CYP3A4 pathway (19). Maidong is one of the two basic ingredients of Shenmai injection, one of the most widely used herbal medicines in traditional Chinese medicine (TCM) and frequently used to treat atherosclerotic coronary heart disease and viral myocarditis or co-administered with other prescribed medicines in certain circumstances as an organ protector (20,21).…”

Section: Introductionmentioning

confidence: 99%

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Ophiopogon japonicus strains from different cultivation regions exhibit markedly different properties on cytotoxicity, pregnane X receptor activation and cytochrome P450 3A4 induction

Kan

Zhuge

et al. 2015

Biomedical Reports

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Abstract. Maidong, known as Ophiopogon japonicus, is one of the two basic ingredients of Shenmai injection, which is a widely used herbal preparation in traditional Chinese medicine (TCM) for the treatment of atherosclerotic coronary heart disease and viral myocarditis. Previously, the ethanol extract of Maidong activated the pregnane X receptor (PXR) signaling pathway and induced the cytochrome P450 3A4 (CYP3A4) reporter gene and raised the concern of herb-drug interactions (HDIs) when Maidong was used in combination with prescribed drugs metabolized by CYP3A4. Therefore, the present study further investigated and compared the differences of the ethanol and aqueous extracts (ee-and ae-, respectively) of two Maidong strains, known as Zhe Maidong (ZM) and Chuan Maidong (CM). Cytotoxicity, PXR activation and CYP3A4 induction by the 3-(4,5)-dimethylthiahiazo-(-z-y1)-3,5-diphenytetrazoliumromide assay, reporter gene assay and reverse transcription-quantitative polymerase chain reaction analysis were examined. The observations showed that ee-ZM demonstrated a significantly higher cytotoxicity, a relatively weaker PXR activation capability and a markedly stronger CYP3A4-inducing capacity than ee-CM. Compared to ae-CM, ae-ZM exhibited only a slight or no difference on cytotoxicity and CYP3A4 induction, while a significant lower level of PXR activation was apparent. Collectively, Maidong from different producing areas possess different properties upon cytotoxicity and the drug-metabolizing enzyme inducing effect, and attention should be paid to the selection of Maidong strains from different planting regions into TCM preparations for reducing potential adverse reactions and

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Direct purification of tanshinones from Salvia miltiorrhiza Bunge by high‐speed counter‐current chromatography without presaturation of the two‐phase solvent mixture

Jiang

2010

J of Separation Science

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Tanshen, the rhizome of Salvia miltiorrhiza Bunge, is a famous Traditional Chinese Medicine for multiple therapeutic remedies. This work presents the isolation and purification of tanshinone I and tanshinone IIA from the extract of the rhizome of S. miltiorrhiza by using high-speed counter-current chromatography (CCC) without presaturation of the two-phase solvent mixture. The CCC method combines the results of CCC solvent system selection and components analyses of solvent mixture by GC, and thus it is possible to add accurately each individual solvent to prepare single saturated solvent phase without presaturation. The optimum CCC solvent system is a system of hexane-ethyl acetate-ethanol-water (8:2:7:3, v/v), which has been determined by usual solvent system selection and CCC runs. As a result, over 98% pure tanshinone IIA and over 94% pure tanshinone I have been obtained by using less solvent volume. Their structures have been identified by ESI-MS, NMR spectra.

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PXR-mediated transcriptional activation of CYP3A4 by cryptotanshinone and tanshinone IIA

Cited by 61 publications

References 33 publications

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

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

Ophiopogon japonicus strains from different cultivation regions exhibit markedly different properties on cytotoxicity, pregnane X receptor activation and cytochrome P450 3A4 induction

Direct purification of tanshinones from Salvia miltiorrhiza Bunge by high‐speed counter‐current chromatography without presaturation of the two‐phase solvent mixture

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