Isoimperatorin

1 Apium sp. 2 Citrus sp. 3 Dictamnus sp. 4 Ruta sp. 5 Zanthoxylum sp.

Isoimperatorin is a methanolic extract of the roots of Angelica dahurica shows significant inhibitory effects on acetylcholinesterase (AChE) with the IC50 of 74.6 μM.

In Vitro:During a screening program for new agrochemicals from Chinese medicinal herbs, the ethanol extract of Notopterygium incisum rhizomes is found to possess strong nematicidal activity against the two species of nematodes, Bursaphelenchus xylophilus and Meloidogyne incognita. Based on bioactivity-guided fractionation, the four constituents are isolated from the ethanol extract and identified as Columbianetin, Falcarindiol, Falcarinol, and Isoimperatorin. Isoimperatorin also has LC50 values of 21.83 μg/mL against B. xylophilus. When using 15 min UV light treatment, falcarindiol, falcarinol, and isoimperatorin demonstrated almost five times more toxic to the southern root-knot nematodes than in dark treatment while columbianetin showed only two times more toxic. isoimperatorin has been demonstrated to possess insecticidal activity against several insects, such as the cabbage aphid (Brevicoryne brassicae)[2]. Isoimperatorin is identified in the active fraction of Angelica dahurica (AD) extract[3]. Isoimperatorin is usually used as the internal standard (IS)[4].

References:
[1]. Kim DK, et al. Acetylcholinesterase inhibitors from the roots of Angelica dahurica. Arch Pharm Res. 2002 Dec;25(6):856-9. [2]. Liu G, et al. Identification of Nematicidal Constituents of Notopterygium incisum Rhizomes against Bursaphelenchus xylophilus and Meloidogyne incognita. Molecules. 2016 Sep 23;21(10). pii: E1276. [3]. Park EY, et al. Angelica dahurica Extracts Improve Glucose Tolerance through the Activation of GPR119. PLoS One. 2016 Jul 8;11(7):e0158796. [4]. Yu XA, et al. The pharmacokinetics, bioavailability and excretion of bergapten after oral and intravenous administration in rats using high performance liquid chromatography with fluorescence detection. Chem Cent J. 2016 Oct 14;10:62.

The effects of isoimperatorin isolated from Angelicae dahuricae on cyclooxygenase-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells.[Pubmed:18365692]

Arch Pharm Res. 2008 Feb;31(2):210-5.

Isoimperatorin (4-[(3-Methyl-2-butenyl)oxy]-7H-furo[3,2-g][1]benzopyran-7-one) is a medicinal herbal product that is isolated from the dried roots of Angelicae dahuricae. Isoimperatorin inhibits the cyclooxygenase-2 (COX-2) and COX-1-dependent phases of prostaglandin D2 (PGD2) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner, with IC50 values of 10.7 microM and 24 microM, respectively. However, this compound was not able to inhibit COX-1 and 2 protein expression in BMMC that were treated with concentrations of up to 50 microM, which indicates that Isoimperatorin directly inhibits COX-2 activity. Furthermore, this compound consistently inhibited the production of leukotriene C4 (LTC4), as well as the degranulation reaction in BMMC, with an IC50 value of 5.7 microM and 9 microM, respectively, and these effects occurred in a dose dependent fashion. These results demonstrate that Isoimperatorin has a dual cyclooxygenase-2 selective/5-lipoxygenase inhibitory activity, and therefore may provide the basis for novel anti-inflammatory drugs.

Isoimperatorin, cimiside E and 23-O-acetylshengmanol-3-xyloside from Cimicifugae rhizome inhibit TNF-alpha-induced VCAM-1 expression in human endothelial cells: involvement of PPAR-gamma upregulation and PI3K, ERK1/2, and PKC signal pathways.[Pubmed:20937376]

J Ethnopharmacol. 2011 Jan 27;133(2):336-44.

ETHNOPHARMACOLOGICAL RELEVANCE: The methanol extract of Cimicifugae Rhizome has been traditionally used in various disorders including inflammation. AIM OF THE STUDY: The aim of the study is to explore whether anti-inflammatory action of 3 active compounds, two triterpenoid glycosides (cimiside E, 23-O-actylshengmanol-3-xyloside) and one furanocoumarin (Isoimperatorin), isolated from Cimicifugae Rhizome is related with peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression in human umbilical endothelial cell line, EA.hy926 cells. MATERIALS AND METHODS: Cell viability and production of reactive oxygen species were performed. In addition, adhesion of monocyte into endothelial cells and western blot for expression of adhesion molecules and signal proteins were investigated in tumor necrosis factor-alpha (TNF-alpha)-activated cells. RESULTS: Pretreatment of test compounds significantly reduced reactive oxygen species (ROS) production and expression of vascular cell adhesion molecule-1 (VCAM-1), but not intercellular cell adhesion molecule-1 (ICAM-1). Three compounds all dose-dependently increased not only PPAR-gamma expression in EA.hy926 cells but inhibited TNF-alpha-induced phosphorylation of Akt, extracellular-signal-regulated kinase (ERK) and protein kinase C (PKC) with different specificity. Finally, they prevented TNF-alpha-induced adhesion of U937 monocytic cells to EA.hy926 cells. CONCLUSIONS: The present results show that cimiside E, 23-O-actylshengmanol-3-xyloside, Isoimperatorin isolated from Cimicifugae Rhizome selectively inhibits TNF-alpha-induced expression of VCAM-1 at least by upregulation of PPAR-gamma, and signals for ERK1/2, PI3K, and PKC are involved in this effect.

In vitro activity of isoimperatorin, alone and in combination, against Mycobacterium tuberculosis.[Pubmed:24330002]

Lett Appl Microbiol. 2014 Apr;58(4):344-9.

UNLABELLED: Previous studies have shown that Isoimperatorin (IO), a furanocoumarin isolated from several medicinal plants, has antimycobacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294). This study demonstrated that IO has antimycobacterial activity against 2 drug-sensitive and 6 drug-resistant isolates, with minimum inhibitory concentrations (MICs) of 50-100 mug ml(-1) and 100-200 mug ml(-1), respectively. IO exhibited synergistic antimycobacterial effects with rifampin (RMP), isoniazid (INH) and ethambutol (EMB) against 6 drug-resistant strains, with fractional inhibitory concentration index (FICI) values of 0.133-0.472, 0.123-0.475 and 0.124-0.25, respectively. The IO/RMP, IO/INH and IO/EMB combination treatments had synergistic effects or no interaction in the 2 drug-sensitive strains and the standard strain ATCC 27294. The synergism of combined drugs against drug-resistant strains was better than drug-sensitive strains. No antagonism was observed in with the aforementioned combinations against all strains tested. IO exhibited relatively low cytotoxicity to Vero cells. Our results indicate that IO may serve as promising a template for future antimycobacterial drug development. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the in vitro synergistic antimycobacterial effects of Isoimperatorin (IO) in combination with three first-line drugs: rifampin (RMP), isoniazid (INH) and ethambutol (EMB). The results indicated that the antimycobacterial activity of IO was modest; however, IO was a useful and effective agent against Myco. tuberculosis when it was combined with first-line antimycobacterial drugs and is worthy of further development as a lead compound for the development of novel antimycobacterial therapeutic agents.

Potent protective effect of isoimperatorin against aflatoxin B1-inducible cytotoxicity in H4IIE cells: bifunctional effects on glutathione S-transferase and CYP1A.[Pubmed:16829687]

Carcinogenesis. 2006 Dec;27(12):2483-90.

Typically chemopreventive agents either induce phase II detoxifying enzymes or inhibit the cytochrome P450 enzymes (CYPs) that are required for the metabolism of carcinogens. In this study, we isolated a coumarin compound, Isoimperatorin from Poncirus trifoliata Raf., and studied its protective effects against aflatoxin B1 (AFB1)-induced cytotoxicity in H4IIE cells. Isoimperatorin (>0.3 microM) significantly inhibited the cytotoxic effect of AFB1. CDNB [1-chloro-2,4-dinitrobenzene; glutathine S-transferase (GST) subtype-non-specific] and NBD (7-chloro-4-nitrobenzo-2-oxa-1,3-diazole; GSTalpha type-specific) assays revealed that Isoimperatorin (0.3-3 microM) increased GST activity in a concentration-dependent manner. Western blot analyses using subtype-specific antibodies confirmed that GSTalpha protein, but not GSTmu or GSTpi, was induced in cells treated with Isoimperatorin. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays revealed that GSTalpha induction by Isoimperatorin is associated with Nrf2/ARE activation. Moreover, ethoxyresorufin-O-deethylase assays showed that Isoimperatorin (2 microM) completely inhibited 3-methylchoranthrene-inducible CYP1A activity. These results indicate that Isoimperatorin from Poncirus trifoliata Raf. possesses a potent hepatoprotective effect against AFB1, presumably through the induction of GSTalpha and the direct inhibition of CYP1A, and suggest that Isoimperatorin should be considered a potential chemopreventive.

[Inhibitory effect of imperatorin and isoimperatorin on activity of cytochrome P450 enzyme in human and rat liver microsomes].[Pubmed:23944042]

Zhongguo Zhong Yao Za Zhi. 2013 Apr;38(8):1237-41.

Imperatorin (IM) and Isoimperatorin (ISOIM) are major active components of common herbal medicines from Umbelliferae plants, and widely used in clinic. This article studies the inhibitory effect of IM and ISOIM on the activity of cytochrome P450 (CYP) enzyme, and assesses their potential drug-drug interaction. IM and ISOIM were incubated separately with human or rat liver microsomes for 30 min, with phenacetin, bupropion, tolbutamide, S-mephenytoin, dextromethorphan and midazolam as probe substrates. Metabolites of the CYP probe substrates were determined by LC-MS/MS, and IC50 values were calculated to assess the inhibitory effect of the two drugs on human CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 enzymes, as well as on rat CYP1A2, 2B6, 2D2 and 3A1/2, and grade their inhibitory intensity. In human liver microsomes, IM and ISOIM showed different inhibitory effects on all of the six CYP isoenzymes. They were strong inhibitors for 1A2 and 2B6. The IC50 values were 0.05 and 0.20 micromol x L(-1) for 1A2, and 0.18 and 1.07 micromol x L(-1) for 2B6, respectively. They also showed moderate inhibitory effect on 2C19, and weak effect on 2C9, 2D6 and 3A4. In rat liver microsomes, IM and ISOIM were identified as moderate inhibitors for 1A2, with IC50 values of 1.95 and 2.98 micromol x L(-1). They were moderate and weak inhibitors for 2B6, with IC50 values of 6.22 and 21.71 micromol x L(-1), respectively. They also had weaker inhibitory effect on 2D2 and 3A1/2. The results indicated that IM and ISOIM had extensive inhibitory effects on human CYP enzymes. They are strong inhibitors of CYP1 A2 and 2B6 enzymes. However, it is worth noting the interaction arising from the inhibitory effect of CYP enzymes in clinic.

Isoimperatorin is a methanolic extract of the roots of Angelica dahurica shows significant inhibitory effects on acetylcholinesterase (AChE) with the IC50 of 74.6 μM.

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