Identification of the Active Components in Shenmai Injection that Differentially Affect Cyp3a4-Mediated 1′-Hydroxylation and 4-Hydroxylation of Midazolam

Zeng, Caiwen; He, Fang; Xia, Chunhua; Zhang, Hong; Xiong, Yu-Qing

doi:10.1124/dmd.112.048025

Cited by 15 publications

(9 citation statements)

References 26 publications

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“…dmd.aspetjournals.org modulators could exert different effects on each metabolite formation (Xia et al, 2009;Dong et al, 2011). As reported, erlotinib and panaxytriol, an active component in Shenmai injection (Zeng et al, 2013), both showed significant activation on MDZ 19-hydroxylation, whereas the activation but not inhibition made it difficult for the in vivo extrapolation. Moreover, either glucuronidation of hydroxylmidazolam or direct glucuronidation of MDZ occurs in vitro and in vivo (Klieber et al, 2008;Hyland et al, 2009;Seo et al, 2010).…”

Section: Discussionmentioning

confidence: 83%

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Cao

Zhang

et al. 2013

Drug Metab Dispos

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To accurately predict the modifications done during metabolic processes by cytochrome P450 (P450) 3A enzyme, selecting substrates that best represent a broad range of substrate substitutions and that follow the Michaelis-Menten kinetic properties is highly necessary. In the present study, the oxidative pathways of deoxyschizandrin (DS), the most abundant lignan in Fructus Schisandrae fruit extract, were characterized with liver microsomes from human (HLM) and rat (RLM). Only one monohydroxylated metabolite 7(S)-hydroxylated metabolite (isoschizandrin, ISZ), was identified using liquid chromatography-mass spectrometry and nuclear magnetic resonance techniques. CYP3A4 and CYP3A5 were found to be the major isoforms involved in the monohydroxylation of DS. Also, the kinetic studies showed that DS hydroxylation obeyed MichaelisMenten kinetics both in HLM and in RLM. However, the subsequent metabolism of ISZ was nearly nonexistent when DS was present. More importantly, the interactions between DS and three well characterized CYP3A probe substrates, testosterone (TST), midazolam (MDZ), and nifedipine (NIF), were studied. TST and MDZ were shown to compete with DS for the mutual binding site, causing K m to be increased. The presence of DS also lowered the binding affinities for MDZ and TST. However, DS showed only slight inhibitory effects on nifedipine (NIF) oxidation even though NIF was able to inhibit DS hydroxylation in a noncompetitive fashion. These results show that DS is a good representative substrate of MDZ and TST primarily due to their shared, large binding regions on CYP3A. Therefore, DS is an attractive candidate as a novel CYP3A probe substrate for predicting the metabolic modifications in CYP3A activity.

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Section: Discussionmentioning

confidence: 83%

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Cao

Zhang

et al. 2013

Drug Metab Dispos

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“…In our previous study, panaxytriol showed differential effect on the metabolic pathways of MDZ, significantly inscreasing MDZ 1′-hydroxylation but inhibiting MDZ 4-hydroxylation. 11,12) This results revealed that PXT had the potential to inhibit or activate the CYP3A4 enzyme activity. Therefore, it is necessary to further study the impact mechanism of PXT on CYP3A4 enzyme and possible interaction with other clinical drugs.…”

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confidence: 79%

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Zhang

Zeng

et al. 2015

Biological & Pharmaceutical Bulletin

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In our previous study, panaxytriol (PXT) was shown to enhance midazolam (MDZ) 1′-hydroxylation significantly but to inhibit MDZ 4-hydroxylation. To explore the underlying mechanism, we investigated the effects of PXT on cytochrome P450 3A (CYP3A)-mediated MDZ metabolic pathways using rat liver microsomes (RLM), human liver microsomes (HLM), and rat primary hepatocytes. In the presence of PXT, the V max of 4-OH MDZ decreased from 0.72 to 0.51 nmol/min·mg pro in RLM and from 0.32 to 0.12 nmol/ min·mg pro in HLM, and the K m value increased from 5.12 to 7.26 µM in RLM and from 27.87 to 32.80 µM in HLM. But the presence of PXT reduced the K m and increased the V max values of MDZ 1′-hydroxylation in RLM and HLM. Interestingly, the differential effect of PXT on MDZ 4-hydroxylation and 1′-hydroxylation was also observed in primary rat hepatocytes after 45-min culture. PXT did not affect the expression levels of CYP3A1/2 mRNA in rat hepatocytes. With extension of the culture time to 6 h, however, PXT significantly inhibited both MDZ 4-hydroxylation and 1′-hydroxylation, and the expression level of CYP3A1/2 mRNA was decreased to 87% and 80% (CYP3A1) and to 89% and 85% (CYP3A2) of those in controls in the presence of PXT 4.0 and 8.0 µg/mL, respectively. These results suggest that PXT could activate MDZ 1′-hydroxylation but inhibit MDZ 4-hydroxylation by changing the CYP3A enzyme affinity and metabolic rate after a shortterm intervention. However, long-term treatment with PXT could inhibit both the 4-hydroxylation and 1′-hydroxylation of MDZ by downregulating CYP3A1/2 mRNA expression.Key words panaxytriol; midazolam hydroxylation metabolism; cytochrome P450 3A; differential effect mechanism Cytochrome P450 (CYP450) is a superfamily of hemeproteins that involved in the biotransformation of the majority of clinical drugs. The inhibition or induction effect of clinical drugs on CYP450 is considered as one of the important factors leading to potential drug-drug interactions.1-3) CYP3A4 is one of the primary CYP450 enzymes in human liver and catalyzes the metabolism of more than 50% of clinical drugs including terfenadine, theophylline and astemizole, etc. Midazolam (MDZ) is the specific substrate of CYP3A4 enzyme and is mainly metabolized to 4-hydroxymidazolam (4-OH MDZ) and 1′-hydroxymidazolam (1′-OH MDZ) by combining with the two different sites of CYP3A4 enzyme active center.4,5) Therefore, the formation of the two metabolites are often simultaneously quantified for the assessment of CYP3A4 activity.Traditional Chinese medicine is widely used in clinical practice in China because of the advantages of good curative effect and less adverse reaction. The incidence of Chinese medicine and chemical medicine interactions significantly increased as the widely using of Chinese medicine, and the change of CYP450 enzyme activity is the principal cause resulting in drug metabolic interactions. 6,7) As a well known study, salvia extract exhibited a marked inhibition effect on the expression of CYP3A4 and CYP1A2 mRNA in HepG2, and high...

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“…Shenmai injection, an injection made of Renshen (Panax ginseng) and Maidong (Ophiopogon japonicus), is commonly used to treat atherosclerotic coronary heart disease and viral myocarditis (20). Currently, it has been also widely applied in clinical practice as an organ protector (21).…”

Section: Discussionmentioning

confidence: 99%

“…Generally, Shenmai injection is considered effective and safe for clinical application. However, it was reported that Shenmai injection could inhibit the activities of hepatic CYP3A1/2 and CYP2C6 (25) and differentially affect CYP3A4-mediated 1'-hydroxylation and 4-hydroxylation of midazolam (20), suggesting potential HDIs could occur when it is co-used with other therapeutic drugs. Our previous study screened the ethanol extracts of 28 commonly used herb medicines and 34 bioactive components from these herb medicines for their capability to activate the PXR-CYP3A4 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…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). Recently, our previous study screened and identified that the ethanol extract of Maidong activated the PXR-CYP3A4 pathway using a reporter gene system, suggesting the possible HDIs when Maidong or Maidong-related preparations are co-used with prescribed drugs metabolized by CYP3A4 (22).…”

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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Identification of the Active Components in Shenmai Injection that Differentially Affect Cyp3a4-Mediated 1′-Hydroxylation and 4-Hydroxylation of Midazolam

Cited by 15 publications

References 26 publications

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Deoxyschizandrin, a Naturally Occurring Lignan, Is a Specific Probe Substrate of Human Cytochrome P450 3A

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

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

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