Imperatorin is a secondary metabolite found in plants that is a member of the coumarin family, namely the furanocoumarins. Imperatorin acts through α1β2η2S receptors to increase GABA-induced chloride currents (IGABA). At 100 μmol and 300 μmol, respectively, imperatorin increased IGABA by 50.5±16.3% and 109.8±37.7%. In vitro, [3H]diazepam's binding to the benzodiazepine site of the GABAA receptor in rat brain is inhibited by both Phellopterin and Imperatorin, which are both present in resveratrol root. Imperatorin's IC50 is 12.3 μmol, while Phellopterin's is There is a 400 nmol IC50. By permanently attaching to the GABA-T active site, imperatorin strongly and irreversibly inhibits GABA-T at concentrations ranging from 3.5 to 14 mmol in a way that is dependent on time and concentration. Imperatorin functions as a dose-dependent reversible inhibitor of acetylcholinesterase (AChE). Utilizing spectrophotometry, the AChE and BChE inhibitory properties of imperatorin and crude extract from Angelica sinensis fruit were examined at doses of 12.5, 25, 50, and 100 μg/mL. The inhibitory impact of imperatorin on AChE is low (13.75-46.11%), while it is significant (37.46-83.98%) on BChE. The IC50 of 31.4 μmol for BChE indicated that imperatorin was selective for BChE but not AChE. The most effective BACE-1 inhibitors were discovered to be imperatorin and (+)-Byakangelicol, with IC50 values of 91.8 and 104.9 μmol, respectively. Strong NO synthesis inhibition is also exhibited by imperatorin (IC50=9.2 μmol) [1]. Imperatorin, whose EC50 is 12.6±3.2 μM, is a mild agonist of TRPV1, a channel that is implicated in sensing a range of unpleasant stimuli [2].

Imperatorin had anxiolytic effects and enhanced memory at dosages of 10 and 20 mg/kg and 30 minutes post-injection. It also increased learning at two distinct stages: acquisition and consolidation. It has also been demonstrated that acute administration of imperatorin at doses of 10 and 20 mg/kg reduces the anxiogenic effects of nicotine (subcutaneous injection, 0.1 mg/kg). The anticonvulsant effectiveness of carbamazepine against maximal shock-induced seizures was dramatically increased by intraperitoneal injection of imperatorin at doses of 30 and 40 mg/kg. This resulted in a lowering of the ED50 from 10.8 to 6.8 mg/kg (34% reduction) and 6 mg/kg (42% reduction), respectively. Additionally, the total brain concentration of carbamazepine increased by 85% (from 1.260 μg/mL to 2.328 μg/mL) when imperatorin at 30 mg/kg and carbamazepine at 6.8 mg/kg were administered. This increase may have resulted from altered blood barrier permeability or from effects akin to those of multidrug resistance protein inhibitors [1]. A naturally occurring furanocoumarin called imperatorin inhibits the action of acetylcholinesterase and inactivates gamma-aminobutyric acid transaminase. Scopolamine-impaired memory consolidation and acquisition are improved when imperatorin, at doses of 5 and 10 mg/kg, is administered acutely prior to scopolamine injection (1 mg/kg). Additionally, the effects of scopolamine on memory acquisition were greatly reduced by the maximum dose of imperatorin (10 mg/kg), which was given twice a day for seven days. In contrast, doses of 5 and 10 mg/kg of furanocoumarins had the same effect. efficient when memory is improved. Measurement is consolidation [3].

Absorption, Distribution and Excretion
A rapid and sensitive assay for the quantification of imperatorin in plasma and tissues has been developed. An analysis was performed by gas chromatography/mass spectrometry in the selected ion-monitoring mode. The main pharmacokinetic parameters obtained were T(max) = 1.23 +/- 0.26 hr, C(max) = 0.95 +/- 0.38 ug/mL, AUC = 3.42 +/- 0.52 hr ug/mL and K(a) = 1.34 +/- 0.18 hr. The experimental results showed that imperatorin was easily absorbed, but its elimination was slow, from 3 to 12 hr after oral administration. The concentrations of imperatorin in rat liver, kidney, lung, and heart were higher than those in other organs. To determine the free fraction in serum, samples were filtered using ultrafiltration membranes with a molecular weight cut-off of 10 kDa, and extracted using liquid-liquid extraction. The protein binding values in rat plasma, spontaneous hypertensive rat plasma, human plasma and human serum albumin were 84 +/- 3, 69 +/- 7, 81 +/- 7 and 75 +/- 3%, respectively.
In this study, a simple and sensitive gas chromatography-mass spectrometry method was developed for the study of bioavailability and protein binding and the metabolism of imperatorin in rat. The results showed that the pharmacokinetics of imperatorin after intravenous and oral administration in rats exhibited linear characteristics. The absolute bioavailability of imperatorin was calculated as approximately 3.85, approximately 33.51 and approximately 34.76% for 6.25, 12.5 and 25 mg/kg, respectively. The low bioavailability of imperatorin may be attributed to the poor absorption or extensive metabolism. The phase I metabolites of imperatorin formed in vitro by rat liver microsomes were studied, and two metabolites were isolated and identified as xanthotoxol and heraclenin. Following oral administration of imperatorin, one metabolite (heraclenin) was detected in rat plasma, and two potential metabolites (xanthotoxol and heraclenin) were detected in rat urine. However, none of potential metabolites was detected in rat feces and bile. The results showed that the metabolites of imperatorin were excreted by kidney, and heraclenin was associated with an active component. Demethylation and oxygenization were the main metabolic pathways. In vitro plasma protein binding of imperatorin was 90.1 and 92.6% for the spiked rat plasma concentrations of 1.0 and 50.0 ug/mL, respectively, indicating that imperatorin showed slow distribution into the intra- and extracellular space.

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Metabolism / Metabolites
Imperatorin (IMP) is a major constituent of many herbal medicines and possesses anti-osteoporosis activity. The present research work aimed to study the biotransformation processes of IMP and evaluated the anti-osteoporosis activity of the transformed metabolites. Among 18 strains of filamentous fungi screened, Penicillium janthinellum AS 3.510 exhibited good capability to metabolize IMP to the new derivatives. Ten transformed products were isolated and purified, and their structures were identified accurately based on spectroscopic data. Eight metabolites (2-8 and 10) were novel and previously unreported. The major biotransformation reactions involved hydroxylation of the prenyloxy side-chain and the lactone ring-opening reaction of furocoumarin skeleton. In addition, anti-osteoporosis activities of all products (1-10) were evaluated using MC3T3-E1 cells. The results showed that products 5 and 8 had the best bioactivities in increasing MC3T3-E1 cell growth. These products could be used in future therapeutic regimens for treating osteoporosis.
In this study, a simple and sensitive gas chromatography-mass spectrometry method was developed for the study of bioavailability and protein binding and the metabolism of imperatorin in rat. The results showed that the pharmacokinetics of imperatorin after intravenous and oral administration in rats exhibited linear characteristics. The absolute bioavailability of imperatorin was calculated as approximately 3.85, approximately 33.51 and approximately 34.76% for 6.25, 12.5 and 25 mg/kg, respectively. The low bioavailability of imperatorin may be attributed to the poor absorption or extensive metabolism. The phase I metabolites of imperatorin formed in vitro by rat liver microsomes were studied, and two metabolites were isolated and identified as xanthotoxol and heraclenin. Following oral administration of imperatorin, one metabolite (heraclenin) was detected in rat plasma, and two potential metabolites (xanthotoxol and heraclenin) were detected in rat urine. However, none of potential metabolites was detected in rat feces and bile. The results showed that the metabolites of imperatorin were excreted by kidney, and heraclenin was associated with an active component. Demethylation and oxygenization were the main metabolic pathways. In vitro plasma protein binding of imperatorin was 90.1 and 92.6% for the spiked rat plasma concentrations of 1.0 and 50.0 ug/mL, respectively, indicating that imperatorin showed slow distribution into the intra- and extracellular space.
Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some organophosphates through hydrolysis. PON1 hydrolyzes the active metabolites in several organophosphates insecticides as well as, nerve agents such as soman, sarin, and VX. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of OP exposure.

Toxicity Summary
IDENTIFICATION AND USE: Imperatorin is a furacoumarin isolated from fruits of Angelica archangelica. It has been tested as an experimental medication. HUMAN STUDIES: Imperatorin was phototoxic and the photomutagenic in human lymphocytes. Imperatorin induced structural chromosome aberrations and sister-chromatid exchanges in human lymphocytes in vitro. ANIMAL STUDIES: Imperatorin produced the anticonvulsant effect in mice. No lesions were observed in the livers of rats treated with imperatorin. Imperatorin induced mutations in Chinese hamster V79 cells and at the ouabain locus in mouse C3H/1OT1/2 cells. Imperatorin was phototoxic and photomutagenic when tested in Chlamydomonas reinhardii. Imperatorin was mutagenic in Ames tester strains (TA92, TA97, TA98, TA100), but not in TA94 and TA102. Mutagenicity was highest in TA98 and TA100. Microsomal activation was not required for mutagenicity. Imperatorin displayed anti-inflammatory and antioxidant activities when tested in vivo and in vitro.
Imperatorin is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen. The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579).

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Interactions
The influence of imperatorin (IMP) on the anticonvulsant activity and acute adverse-effect potential of lamotrigine (LTG, a second generation antiepileptic drug) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice. In order to assess the nature of interaction between IMP and LTG in the MES test, total brain LTG concentrations were evaluated with high-pressure liquid chromatography (HPLC). Results indicate that IMP administered ip, 30 min before the test, at a dose of 50 mg/kg significantly enhanced the anticonvulsant action of LTG in the MES test by reducing the median effective dose (ED(50)) of LTG from 6.11 to 2.47 mg/kg (p < 0.05). In contrast, IMP administered ip at doses of 30 and 40 mg/kg did not significantly potentiate the anticonvulsant activity of LTG against MES induced seizures, although a reduction of the ED(50) values for LTG from 6.11 to 5.77, and 4.28 mg/kg, respectively, was observed. On the other hand, IMP administered ip, at doses of 30, 40 and 50 mg/kg had no impact on the acute adverse effects of LTG, and the median toxic doses for LTG (TD(50)) were almost unchanged, ranging from 22.13 to 30.04 mg/kg in the chimney test. The protective index (TD(50) to ED(50) ratio) for LTG administered alone was 4.90 and increased to 5.21, 6.77, and 8.96 for LTG in combination with IMPat doses of 30, 40 and 50 mg/kg, respectively. Pharmacokinetic evaluation of total brain LTG concentration with HPLC revealed that IMP at the dose of 50 mg/kg did not affect total brain LTG concentration in experimental animals and thus, the observed interaction between IMP and LTG in the MES test was pharmacodynamic in nature. The present study demonstrates that IMP ameliorates the pharmacological profile of LTG, when considering both, the antiseizure and acute adverse effects of the drug in preclinical study on animals. The combination of LTG with IMP can be of pivotal importance for epileptic patients as a potentially advantageous combination if it is proven that the results of this study can be extrapolated to clinical settings.
BACKGROUND AND PURPOSE: Herbs which are widely used as food and medicine, are involved in many physiopathological processes. Melatonin is a human hormone, synthesized and secreted by the pineal gland, with a range of biological functions. Here, we have evaluated the potential influences of components extracted from common herbs on melatonin metabolism in humans. EXPERIMENTAL APPROACH: An in vivo pharmacokinetic study involving 12 healthy subjects, in vitro incubations with human liver microsomes (HLMs) and recombinant human cytochrome P (CYP) isoenzymes and an in silico quantitative structure-activity relationship (QSAR) model analysis using comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to explore these interactions. KEY RESULTS: After systematic screening of 66 common herbs, Angelica dahurica exhibited the most potent inhibition of melatonin metabolism in vitro. The in vivo pharmacokinetic study indicated inhibition of melatonin metabolism, with approximately 12- and 4-fold increases in the AUC and Cmax of melatonin in human subjects. Coumarins from A. dahurica, including imperatorin, isoimperatorin, phellopterin, 5-methoxypsoralen and 8-methoxypsoralen, markedly inhibited melatonin metabolism with Ki values of 14.5 nM, 38.8 nM, 6.34 nM, 5.34 nM and 18 nM respectively, through inhibition of CYP 1A2, 1A1 and 1B1 in HLMs. A QSAR model was established and satisfactorily predicted the potential risk of coumarins for inhibition of melatonin metabolism in vivo. CONCLUSION AND IMPLICATIONS: Coumarins from A. dahurica inhibited melatonin metabolism in vivo and in vitro. Our findings provide vital guidance for the clinical use of melatonin.
Naturally occurring coumarins (NOCs) are anti-carcinogenic in the mouse skin model. To characterize the chemopreventive potential of NOCs against breast cancer, we first examined their effects on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation in mouse mammary gland. We hypothesized that those NOCs that both inhibited cytochrome P450 1A1/1B1 and induced hepatic glutathione S-transferases (GSTs) would be the most effective in blocking DMBA-DNA adduct formation in mouse mammary gland. To address this hypothesis, simple coumarins (e.g. coumarin and limettin, which induced mouse hepatic GSTs but had little effect on P4501A1/1B1) and linear furanocoumarins (e.g. imperatorin and isopimpinellin, which induced hepatic GSTs and were potent inhibitors of P4501A1/1B1) were compared. Mice were pretreated with NOCs (150 mg/kg body wt, by gavage) prior to either a single dose of DMBA (50 ug) or multiple doses of DMBA (20 ug daily for 3 and 6 weeks). Mammary DMBA-DNA adduct formation was quantitated by the nuclease P1-enhanced 32P-postlabeling assay. With the single dose of DMBA, coumarin, limettin, imperatorin and isopimpinellin inhibited DMBA-DNA adduct formation by 50, 41, 79 and 88%, respectively. Coumarin, limettin and imperatorin blocked DMBA-DNA adduct formation by 36, 60, and 66% at 3 weeks, and by 0, 49 and 55% at 6 weeks of DMBA dosing, respectively. In a 6 week dose-response study of select NOCs and 7,8-benzoflavone (a potent P4501 inhibitor that had little effect on GSTs), DMBA-DNA adduct formation was inhibited by 0, 43 and 24% in the limettin groups; by 26, 26 and 69% in the isopimpinellin groups; and by 80, 96 and 97% in the 7,8- benzoflavone groups at 35, 70 and 150 mg/kg, respectively. Taken together, these results suggest that linear furanocoumarins had a greater inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared with simple coumarins, and that the predominant effect may be P4501 inhibition.
Several naturally occurring coumarins previously found to be potent inhibitors of mouse hepatic ethoxyresorufin-O-deethylase (EROD) and/or pentoxyresorufin-O-dealkylase (PROD) were examined for their effects on formation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) DNA adducts in mouse epidermis, as well as, their effects on skin tumor initiation by these polycyclic aromatic hydrocarbons (PAH). Bergamottin, a potent inhibitor of hepatic EROD, given topically 5 min prior to an initiating dose of B[a]P, significantly decreased total covalent binding of B[a]P to DNA in a dose-dependent manner 24 hr after treatment. A dose of 400 nmol bergamottin reduced covalent binding of B[a]P by 72%. Coriandrin, at a dose of 400 nmol also significantly reduced total covalent binding of B[a]P by 59%. In addition, formation of the major (+)anti-B[a]P-diol epoxide-N2-dGuo adduct was selectively reduced by both of these coumarins. In contrast, bergamottin and coriandrin did not significantly decrease covalent binding of DMBA to epidermal DNA at doses of either 400 nmol or 800 nmol. Imperatorin and isopimpinellin, which are more potent inhibitors of hepatic PROD activity, significantly reduced overall binding of DMBA to epidermal DNA by 67% and 52%, respectively, when applied at doses of 400 nmol. These two coumarins also inhibited B[a]P-DNA adduct formation at similar doses but to a lesser extent. Imperatorin at a dose of 400 nmol dramatically decreased formation of covalent DNA adducts derived from both the anti and syn diol epoxides of DMBA. Bergamottin was a potent inhibitor of tumor initiation by B[a]P while coriandrin was less effective in this regard. Imperatorin was an effective inhibitor of skin tumor initiation by DMBA and also inhibited complete carcinogenesis by this PAH. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B[a]P. The results demonstrate that several naturally occurring coumarins possess the ability to block DNA adduct formation and tumor initiation by PAHs such as B[a]P and DMBA. The mechanism for reduced DNA adduct formation and tumor initiation appears to involve inhibition of the P450s involved in the metabolic activation of these hydrocarbons. Finally, the differential effects of certain coumarins on B[a]P vs DMBA DNA adduct formation and tumor initiation may be useful for dissecting the role of specific cytochromes P450 in their metabolic activation.
For more Interactions (Complete) data for Imperatorin (11 total), please visit the HSDB record page.

[1]. Imperatorin-pharmacological meaning and analytical clues: profound investigation. Phytochem Rev. 2016;15:627-649.

[2]. Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem. 2014 Apr 4;289(14):9600-10.

[3]. Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice. Psychopharmacology (Berl). 2015 Mar;232(5):931-42.

Therapeutic Uses
/EXPL THER/ Several naturally occurring coumarins, to which humans are routinely exposed in the diet, were previously found to inhibit P450-mediated metabolism of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in vitro, block DNA adduct formation in mouse epidermis and inhibit skin tumor initiation by B[a]P and/or DMBA when applied topically to mice. The present study was designed to investigate the effects of two of these compounds, of the linear furanocoumarin type, when given orally (70 mg/kg per os, four successive daily doses), on P450 and glutathione S-transferase (GST) activities and DNA adduct formation by B[a]P and DMBA in various mouse tissues. Imperatorin and isopimpinellin significantly blocked ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O:-dealkylase (PROD) activities in epidermis at 1 and 24 hr after oral dosing. Imperatorin and isopimpinellin modestly inhibited EROD activities in lung and forestomach at 1 hr and significantly inhibited PROD activities in lung and forestomach at 1 hr after the final oral dose. Twenty-four hours after the final oral dose of imperatorin or isopimpinellin EROD and PROD activities remained inhibited in epidermis and lung. However, forestomach P450 activity had returned to control levels. Interestingly, imperatorin and isopimpinellin treatment inhibited liver EROD activity at 1 hr, had no effect on PROD activity at this time point, but elevated both these enzyme activities at 24 hr. Elevated EROD and PROD activities coincided with elevated hepatic P450 content. Imperatorin and isopimpinellin treatment also increased liver cytosolic GST activity at both 1 and 24 hr after the final oral dose by 1.6-fold compared with corn oil controls. Oral administration of imperatorin and isopimpinellin also had a protective effect against DNA adduct formation by B[a]P and DMBA. Imperatorin pretreatment decreased formation of DNA adducts by DMBA in forestomach. Pretreatment with isopimpinellin led to reduced DNA adduct levels in liver (B[a]P), lung (B[a]P) and mammary epithelial cells (DMBA). These results suggest that imperatorin and isopimpinellin may have potential chemopreventive effects when administered in the diet.
/EXPL THER/ Augmented endothelial nitric oxide (NO) synthase (eNOS) signaling has been reported to be associated with improvements in cardiac remodeling, and NO levels have been shown to be related to cardiac hypertrophy and heart failure. Imperatorin, a dietary furanocoumarin, has been shown to prevent cardiac hypertrophy in the spontaneous hypertension rats (SHR). Thus, we aimed to clarify whether imperatorin attenuates both cardiac hypertrophy and heart failure via the NO-signaling pathway. In neonatal mouse cardiac myocytes, imperatorin inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was unchanged by NG-nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) on Kunming (KM) male mice, the ratio of heart weight to body weight was lower after imperatorin treatment than in controls (6.60 +/- 0.35 mg/g in TAC, 4.54 +/- 0.29 mg/g with imperatorin 15 mg kg(-1)d(-1), ig, P<0.01); similar changes in the ratio of lung weight to body weight (7.30 +/- 0.85 mg/g in TAC, 5.42 +/- 0.51 mg/g with imperatorin 15 mg/kg/d, ig) and the myocardial fibrosis. All of these improvements were blunted by L-NAME. Imperatorin treatment significantly activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the imperatorin-treated ones. Imperatorin can attenuate cardiac hypertrophy both in vivo and in vitro, and halt the process leading from hypertrophy to heart failure by a NO-mediated pathway.
/EXPL THER/ The influence of imperatorin (IMP) on the anticonvulsant activity and acute adverse-effect potential of lamotrigine (LTG, a second generation antiepileptic drug) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice. In order to assess the nature of interaction between IMP and LTG in the MES test, total brain LTG concentrations were evaluated with high-pressure liquid chromatography (HPLC). Results indicate that IMP administered ip, 30 min before the test, at a dose of 50 mg/kg significantly enhanced the anticonvulsant action of LTG in the MES test by reducing the median effective dose (ED(50)) of LTG from 6.11 to 2.47 mg/kg (p < 0.05). In contrast, IMP administered ip at doses of 30 and 40 mg/kg did not significantly potentiate the anticonvulsant activity of LTG against MES induced seizures, although a reduction of the ED(50) values for LTG from 6.11 to 5.77, and 4.28 mg/kg, respectively, was observed. On the other hand, IMP administered ip, at doses of 30, 40 and 50 mg/kg had no impact on the acute adverse effects of LTG, and the median toxic doses for LTG (TD(50)) were almost unchanged, ranging from 22.13 to 30.04 mg/kg in the chimney test. The protective index (TD(50) to ED(50) ratio) for LTG administered alone was 4.90 and increased to 5.21, 6.77, and 8.96 for LTG in combination with IMPat doses of 30, 40 and 50 mg/kg, respectively. Pharmacokinetic evaluation of total brain LTG concentration with HPLC revealed that IMP at the dose of 50 mg/kg did not affect total brain LTG concentration in experimental animals and thus, the observed interaction between IMP and LTG in the MES test was pharmacodynamic in nature. The present study demonstrates that IMP ameliorates the pharmacological profile of LTG, when considering both, the antiseizure and acute adverse effects of the drug in preclinical study on animals. The combination of LTG with IMP can be of pivotal importance for epileptic patients as a potentially advantageous combination if it is proven that the results of this study can be extrapolated to clinical settings.
/EXPL THER/ BACKGROUND: Imperatorin (IM) is a furanocoumarin isolated from the root of Angelica dahurica, which is reported to have anticonvulsant and anticancer effects. In this study, the antiproliferative effect of IM on 9 human cancer cell lines was examined, and human hepatoma HepG2 cells were chosen as the target for preferential killing by IM. Particularly, the mechanism of IM-induced apoptosis and in vivo animal effects were also studied. METHODS: Cell viability was measured using MTT assay, and apoptosis was detected by Hoechst staining, annexin V-PI staining, and DNA laddering assay. Mitochondrial membrane potential was detected by JC-1 staining. Western blot analysis was employed to detect the expression of apoptosis-related proteins. In addition, the in vivo anticancer effect of IM was examined in nude mice bearing HepG2 cells. RESULTS: IM inhibited the proliferation of HepG2 cells through apoptosis induction in a time- and dose-dependent manner by observation of the nuclear morphology, DNA fragmentation, phosphatidylserine externalization, loss of mitochondrial membrane potential, release of cytochrome c into cytosol, and activation of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase cleavage. As cell death could partly be prevented by the caspase-8 or caspase-9 inhibitor and was evidenced by the results of Western blot analysis, our results also suggest that IM-induced apoptosis is mediated through both death receptor and mitochondrial pathways. In the animal model, IM was found to effectively suppress tumor growth by 31.93 and 63.18% at dosages of 50 and 100 mg/kg, respectively, after treatment for 14 days. No significant weight loss or toxicity to the hosts was found. CONCLUSIONS: IM can function as a cancer suppressor by inducing apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways. Furthermore, the in vivo antitumor activities of IM are significant with negligible weight loss and damage to the host.
For more Therapeutic Uses (Complete) data for Imperatorin (9 total), please visit the HSDB record page.

C16H14O4

270.284

270.089

482-44-0

10212

White to off-white solid powder

1.2±0.1 g/cm3

448.3±45.0 °C at 760 mmHg

98-100ºC

224.9±28.7 °C

0.0±1.1 mmHg at 25°C

1.606

3.81

0

4

3

20

436

0

O(C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H])C1=C2C(C([H])=C([H])C(=O)O2)=C([H])C2C([H])=C([H])OC1=2

OLOOJGVNMBJLLR-UHFFFAOYSA-N

InChI=1S/C16H14O4/c1-10(2)5-7-19-16-14-12(6-8-18-14)9-11-3-4-13(17)20-15(11)16/h3-6,8-9H,7H2,1-2H3

9-(3-methylbut-2-enoxy)furo[3,2-g]chromen-7-one

Ammidin MarmelosinImperatorin Pentosalen

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~184.99 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.25 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)