9-(3-メチル-2-ブテニルオキシ)-7H-フロ[3,2-g][1]ベンゾピラン-7-オン

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Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

Appropriate engineering controls: General industrial hygiene practice.

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If the compound has been ingested, rapid gastric lavage should be performed using 5% sodium bicarbonate. For skin contact, the skin should be washed with soap and water. If the compound has entered the eyes, they should be washed with large quantities of isotonic saline or water. In serious cases, atropine and/or pralidoxime should be administered. Anti-cholinergic drugs work to counteract the effects of excess acetylcholine and reactivate AChE. Atropine can be used as an antidote in conjunction with pralidoxime or other pyridinium oximes (such as trimedoxime or obidoxime), though the use of '-oximes' has been found to be of no benefit, or possibly harmful, in at least two meta-analyses. Atropine is a muscarinic antagonist, and thus blocks the action of acetylcholine peripherally.

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.

Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides. The furocoumarin 8-methoxypsoralen is carcinogenic to humans, and possibly 5-methoxypsoralen as well (L135). There is some evidence from mouse studies that other furocoumarins are carcinogenic when combined with exposure to UVA radiation (A15105). The SKLM regards the additional risk of skin cancer arising from the consumption of typical quantities of furocoumarin-containing foods, which remain significantly below the range of phototoxic doses, as insignificant. However, the consumption of phototoxic quantities cannot be ruled out for certain foods, particularly celery and parsnips, that may lead to significant increases in furocoumarin concentrations, depending on the storage, processing and production conditions. (L2157) Furocoumarin photochemotherapy is known to induce a number of side-effects including erythema, edema, hyperpigmentation, and premature aging of skin. All photobiological effects of furocoumarins result from their photochemical reactions. Because many dietary or water soluble furocoumarins are strong inhibitors of cytochrome P450s, they will also cause adverse drug reactions when taken with other drugs. Limited evidence of carcinogenic effect. (L579)

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a structure estimation method(2), indicates that imperatorin is expected to have moderate mobility in soil(SRC). Volatilization of imperatorin from moist soil surfaces is not expected(SRC) given an estimated Henry's Law constant of 6.1X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Imperatorin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2019).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a structure estimation method(2), indicates that imperatorin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 6.1X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Imperatorin is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(3). According to a classification scheme(4), an estimated BCF of 6(SRC), from an estimated log Kow of 1.64(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2019).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), imperatorin, which has an estimated vapor pressure of 2.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase imperatorin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.7 hours(SRC), calculated from its rate constant of 1.4X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). The rate constant for the vapor-phase reaction of imperatorin with ozone has been estimated as 4.3X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). This corresponds to an atmospheric half-life of about 40 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). Reaction with nitrate radicals in the atmosphere may be important(2). Particulate-phase imperatorin may be removed from the air by wet and dry deposition(SRC). Imperatorin absorbs light at 301 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Imperatorin was detected at 16.24-17.00 ppm in lemon oil, it was not detected (detection limit 0.1 ppm) in grapefruit oil(1). Lemon and lime oil contained 326 and 805 mg/L of imperatorin, respectively, it was not detected (detection limit 0.039 mg/L) in bergamot, grapefruit, mandarin or bitter orange oils(2). Imperatorin was not detected (detection limit 0.40 mg/kg fresh weight) in orange, clementine, lemon, grapefruit, bergamot and pummelo peel extracts(3). Imperatorin was detected in 4 of 12 commercial limoncello liqueur samples at 0.6-4.4 mg/L and in one lemon peel essential oil sample at 60 mg/L(4). In liqueurs and a tea prepared from the Peucedanum ostruthium rhizome (masterwort), imperatorin was detected at 11.69-323.01 and 15.94 ug/mL, respectively(6).

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).

Imperatorin is found in the roots of Glehnia littoralis (Umbelliferae)(1) and Angelica dahurica (Apiaceae)(2). Imperatorin has been isolated from the roots and fruits of Angelica archangelica L. (Apiaceae)(3). Imperatorin was found in large, medium and small fruit, leaf, branch and flower of Citrus grandis Tomentosa harvested from Huazhou, China in 2013(4). In immature seeds of parsnip (Pastinaca sativa), 3.2% of total furanocoumarin compounds was identified as imperatorin(5).

Imperatorin concentrations in various plants(1).

Symptoms of low dose exposure include excessive salivation and eye-watering. Acute dose symptoms include severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Hypertension, hypoglycemia, anxiety, headache, tremor and ataxia may also result.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of imperatorin can be estimated to be 390(SRC). According to a classification scheme(2), this estimated Koc value suggests that imperatorin is expected to have moderate mobility in soil(SRC).

Imperatorin is a compound found in many plants, including plants of the Apiaceae, Rutaceae, Chenopodiaceae and Rosaceae families(1). Imperatrorin is derived from the roots of Imperatoria osthruthium L. Umbelliferae, from seeds of Angelica archajngelica L. and from the fruit of Pastinaca sativa L., Umbelliferae(1). Impertoria is a perennial herbaceous plant, widespread in the mountainous areas of central and southern Europe(3).

Natural flavoring substances and natural adjuvants may be safely used in food in accordance with the following conditions. (a) They are used in the minimum quantity required to produce their intended physical or technical effect and in accordance with all the principles of good manufacturing practice. (b) In the appropriate forms (plant parts, fluid and solid extracts, concentrates, absolutes, oils, gums, balsams, resins, oleoresins, waxes, and distillates) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, previously sanctioned for such use, or regulated in any section of this part. Imperatoria (Scientific name: Peucedanum ostruthium (L.). Koch (Imperatoria ostruthium L.) is included on this list. /Imperatoria/

Found in the roots of Imperatoria osthruthium, seeds of Angelica archangelica, and fruit of Pastinaca sativa; [Merck Index] Dried substance and derivatives used in liqueurs (bitters); [HSDB] A naturally occurring psoralen; [REPROTOX]

MEDICATION

The dried product and its derivatives are used in the formulation of liqueurs (bitters). /Imperatoria/

Extracts from the roots of Peucedanum ostruthium (L) Koch are claimed to have antiphlogistic and antipyretic effects. /Imperatoria/

Imperatorin was found in Yuanhu Zhitong tablet (Chinese medicine).

Imperatorin was found in dried roots and rhizomes of Glehnia littoralis (Umbelliferae) a traditional oriental medicine used as a diaphoretic, antipyretic and analgesic agent in Taiwan.

Imperatorin is a component of Peucedanum ostruthium (L) Koch (masterwort), traditionally used in the alpine region of Austria as an ingredient of liqueurs and bitters and as a herbal drug.