2H-フロ[2,3-h][1]ベンゾピラン-2-オン

If inhaled, remove to fresh air. If not breathing give artificial respiration. If breathing is difficult, give oxygen. If swallowed, wash out mouth with water provided person is conscious. Call physician. In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. (L579)

Photochemical genotoxicity can be detected using appropriately adapted versions of most of the standard in vitro genotoxicity assays. The most sensitive approach to detect potentially photogenotoxic agents seems to be the investigation of DNA damage (DNA strand breakage, chromosomal aberrations, micronuclei) in mammalian cells in vitro. In a previous paper, we proposed the use of the micronucleus assay in Chinese hamster V79 cells for this purpose. This assay was found suitable to detect various photogenotoxic compounds with different photoactivation mechanisms. In order to extend the experimental experiences with this assay, we present here further data from a screening mode testing of 16 different potential photosensitizers. The photoclastogenic and photocytotoxic potential of the compounds was investigated concomitantly. So far, all substances detected in the photo-micronucleus assay as photogenotoxins also exhibited photocytotoxic properties but not vice versa. Among the compounds tested in the present study, tiaprofenic acid, 5-MOP, angelicin, nitrazepam, bendroflumethiazide, and dacarbazine were photogenotoxic and photocytotoxic. Further, 6-mercaptopurine, a metabolite of azathioprine was positive for both endpoints, whereas azathioprine was found negative. Azathioprine seems to be an example of a compound which lacks photo(geno)toxic properties in vitro but may be converted to a photosensitizer by enzymatical metabolization. With the results obtained in this study, the data base for the photo-micronucleus assay was extended to 35 compounds, which were tested using the same protocol and the same irradiation conditions. The photogenotoxicity results of all these compounds are summarized and discussed in correlation to their different photoactivation mechanisms, photocytotoxicity and photocarcinogenicity.

In this study we have found that the crude extract of Psoraleae Fructus inhibited acetylcholinesterase activity in vitro and ameliorated impairment of the inhibitory avoidance response and of the water maze spatial performance caused by scopolamine in rats. Among all fractions, the chloroform fraction showed the best inhibitory effect on acetylcholinesterase activity and could reduce the scopolamine-induced inhibitory avoidance response impairment. Psoralen and isopsoralen, two major constituents of the chloroform fraction of Psoraleae Fructus identified by high performance liquid chromatography, also reduced the extent of the inhibitory avoidance response impairment. The results suggest that psoralen and isopsoralen are the major active ingredients of Psoraleae Fructus responsible for the progressive reversal of scopolamine-induced amnesia, whose effects are partially associated with inhibition of AchE activity and hence activation of the central cholinergic neuronal system.

Monofunctional psoralens, plus UVA radiation are not erythemogenic and are less mutagenic than bifunctional psoralens plus UVA radiation. Thus, they have received considerable attention in recent years as potential therapeutic agents for various skin diseases. The purpose of this study was to examine the immunologic side effects following treatment of mice with a monofunctional psoralen plus UVA radiation. We report that angelicin plus UVA radiation suppressed the induction of contact hypersensitivity to dinitrofluorobenzene. This decreased immune response was associated with the presence of splenic suppressor cells that transferred suppression to normal recipients. Treatment with angelicin and UVA radiation also decreased the number of Thy-1+ and Ia+ dendritic epidermal cells in the treated site. We conclude that although this monofunctional psoralen is not phototoxic, it has immunosuppressive activity in mice.

Because of the undesirable side effects associated with the use of 8-methoxypsoralen and long-wave ultraviolet A (UVA) radiation in the treatment of skin disorders such as psoriasis, the use of monofunctional psoralens, which are less erythemogenic, less mutagenic, and generally non-phototoxic, has received considerable attention. Little is known, however, about the immunosuppressive properties of monofunctional psoralens. The purpose of this study was to examine the effect of parenteral administration of a monofunctional psoralen, angelicin, plus exposure to UVA radiation on the immune response. Injection of angelicin followed by exposure to UVA radiation significantly suppressed delayed-type hypersensitivity to alloantigen in a dose-dependent fashion. Similarly, the capacity of spleen cells from the angelicin and UVA-treated animals to proliferate to alloantigen was significantly suppressed. The suppression was specific for the alloantigen used to sensitize the angelicin and UVA-treated animals and was associated with the appearance of splenic antigen-specific suppressor T lymphocytes. These data demonstrate that the effect of systemic administration of a monofunctional psoralen followed by UVA exposure on the immune response is similar to that seen following the injection of bifunctional psoralens. These findings also suggest that the severe skin phototoxicity associated with the use of a bifunctional psoralen and UVA radiation is not necessary for the induction of systemic immuno-suppression. Furthermore, the induction of systemic antigen-specific immunosuppression by angelicin plus UVA, without overt skin phototoxicity, suggests the possibility of using this and related compounds to specifically inhibit unwanted immune reactions.

For more Interactions (Complete) data for Isopsoralen (12 total), please visit the HSDB record page.

Furocoumarins can cause photosensitization dermatitis especially if these compounds come into contact with the skin. Some furocoumarins, especially bifunctional furocoumarins, are known to be carcinogenic (A15105). 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 102(SRC), determined from a log Kow of 2.08(2) and a regression-derived equation(3), indicates that isopsoralen is expected to have high mobility in soil(SRC). Volatilization of isopsoralen from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.8X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Isopsoralen is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.7X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2019).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 102(SRC), determined from a log Kow of 2.08(2) and a regression-derived equation(3), indicates that isopsoralen is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 6.8X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are 74 days and greater than 1 year, respectively(SRC). According to a classification scheme(5), an estimated BCF of 11(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). 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), isopsoralen, which has an estimated vapor pressure of 9.7X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase isopsoralen 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 9 hours(SRC), calculated from its rate constant of 4.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase isopsoralen is degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be 13 hours(SRC), calculated from its rate constant of 2.1X10-17 cu cm/molecule-sec at 25 °C(SRC) derived using a structure estimation method(2). Particulate-phase isopsoralen may be removed from the air by wet and dry deposition(SRC). Isopsoralen absorbs UV light at wavelengths of 299 nm(3) and, therefore, is expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

IDENTIFICATION AND USE: Isopsoralen is a natural furocoumarin. It has been tested as experimental therapy. HUMAN STUDIES: Isopsoralen acted in vitro as ERalpha receptor agonists and promoted MCF-7 cell proliferation significantly. Angelicin forms DNA monoadducts when photoactivated. In human cells isopsoralen promoted sister-chromatid exchanges. ANIMAL STUDIES: Isopsoralen had potent tranquilizing, anticonvulsant, and central muscle relaxant activity in rats, mice, and rabbits when given both ip and orally. Isopsoralen was photomutagenic in bacterial and animal cells generating DNA monoadducts.

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)

Isopsoralen has been isolated and detected in various Umbelliferae, including angelica (Angelica atropurpurea), parsnip (Pastinaca sativa) and several hogweed (Heracleum) species(1). Isopsoralen has been detected in the fresh fruiting heads of Heracleum mantegazzianum at 292 mg/100g; Isopsoralen has been detected at 0.5 mg/g in the root of H. sphondylium; concentrations in roots of H. laciniatum were circa 0.05 mg/g of root for isopsoralen(1). Isopsoralen is a main active component of Psoralea corylifolia, a traditional Chinese medicine(2,3).

Isopsoralen concentrations in various plants(1).[Table#4633]

Angelicin, a synonym for isopsoralen, concentrations in various plants(1).

The Koc of isopsoralen is estimated as 102(SRC), using a log Kow of 2.08(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that isopsoralen is expected to have high mobility in soil.

Isopsoralen occurs in various plants and plant parts(1). Isopsoralen has been isolated and detected in various Umbelliferae, including angelica (Angelica atropurpurea), parsnip (Pastinaca sativa) and several hogweed (Heracleum) species(2). Isopsoralen has been detected in the fresh fruiting heads of Heracleum mantegazzianum at 292 mg/100g; Isopsoralen has been detected at 0.5 mg/g in the root of H. sphondylium; concentrations in roots of H. laciniatum were circa 0.05 mg/g of root for Isopsoralen(3). Isopsoralen is a main active component of Psoralea corylifolia, a traditional Chinese medicine(3,4), and has antibacterial, anti-inflammatory, and antitumor activities(4).

/ENDOCRINE MODULATION/ The seed of Psoralea corylifolia L. (PCL), a well-known traditional Chinese medicine, has been applied as a tonic or an aphrodisiac agent and commonly used as a remedy for bone fracture, osteomalacia and osteoporosis in China. In our study, the estrogen receptor subtype-selective activities of the extracts and compounds derived from PCL were analyzed using the HeLa cell assay. The different fractions including petroleum ether, CH(2)Cl(2) and EtOAc fractions of the EtOH extract of PCL showed significant activity in activating either ERalpha or ERbeta whereas the n-BuOH fraction showed no estrogenic activity. Further chromatographic purification of the active fractions yielded seven compounds including the two coumarins isopsoralen and psoralen, the four flavonoids isobavachalcone, bavachin, corylifol A and neobavaisoflavone, and the meroterpene phenol, bakuchiol. In reporter gene assay, the two coumarins (10(-8)-10(-5)M) acted as ERalpha-selective agonists while the other compounds (10(-9)-10(-6)M) activated both ERalpha and ERbeta. The estrogenic activities of all compounds could be completely suppressed by the pure estrogen antagonist, ICI 182,780, suggesting that the compounds exert their activities through ER. Only psoralen and isopsoralen as ERalpha agonists promoted MCF-7 cell proliferation significantly. Although all the compounds have estrogenic activity, they may exert different biological effects. In conclusion, both ER subtype-selective and nonselective activities in compounds derived from PCL suggested that PCL could be a new source for selective estrogen-receptor modulators.

/GENOTOXICITY/ The transient nuclease sensitivity of repair patches during excision repair of UV or angelicin damage in T98g cells was independent of the initial distribution of DNA damage in chromatin. Repair patches produced in response to a linker-specific damaging agent became distributed randomly in chromatin, which suggested that nucleosome cores do not necessarily return to their original sites along a DNA strand after the DNA is repaired.

/GENOTOXICITY/ Photoactivated 8-methoxypsoralen (8-MOP) has been proven to be clinically effective for a number of dermatological conditions including lichen planus, mycosis fungoides, and psoriasis. 8-MOP forms two types of covalent photoproducts with DNA, monoadducts, and bifunctional adducts which cross-link the two DNA strands. Angelicin is a congener of 8-MOP which forms only monoadducts. We have used the combined density and isotopic labeling technique to study repair replication in cultured human fibroblasts treated with either of these compounds and exposed to near-ultraviolet light. In human diploid fibroblasts (WI-38), the time course of repair replication for both compounds is similar. Drug concentration and ultraviolet dose responses are also similar for 8-MOP and angelicin. No repair replication was stimulated by either compound in xeroderma pigmentosum cells from Complementation Group A (XP12BE). These results suggest that repair replication in response to 8-MOP is primarily a response to monoadducts and that the enzymatic pathway for this repair synthesis shares at least one step with the pathway for repair of pyrimidine dimers. Cross-link persistence in treated cells was assayed by use of the single-strand-specific S1 nuclease to digest DNA that did not renature readily following heat denaturation. Partial removal of cross-links was observed in normal, xeroderma pigmentosum variant, and Fanconi's anemia fibroblasts, but not in xeroderma pigmentosum Group A cells.

Found in many plants traditionally used as herbal remedies; Highly fluorescent; [HSDB] Present in plants of the Umbelliferae family; Clinically tested in combination with ultraviolet A radiation for the treatment of psoriasis; [IARC]

MEDICATION

Angelicin is used as tranquilliser, sedative, or anticonvulsant. (L579)

We have developed two practical one-step syntheses of 2,3-dihydro-3-hydroxy-2-hydroxyalkylbenzofurans from readily available optically pure alpha,beta-epoxy aldehydes. Electron-deficient resorcinols react with epoxy aldehydes using either Cs2CO3 in DMF or KOH/CaCl2 in MeOH to give adducts 13, 16, 18, 20, 21, and brosimacutin G (6t). Grignard reagents prepared by low-temperature halogen-metal exchange of acetoxy iodocoumarins 35d and 40 and acetoxy bromonaphthalene 41 add to epoxy aldehyde (S)-26 to complete the first syntheses of vaginidiol (7c), vaginol (7t), smyrindiol (8c), xanthoarnol (8t), and avicenol A (9t). Acid-catalyzed fragmentation of vaginidiol or vaginol provides angelicin, while that of smyrindiol or xanthoarnol affords psoralen. In both cases, the trans isomers fragment only twice as fast as the cis isomers, possibly through the intermediacy of a common benzylic cation. This may have implications for the biosynthesis of angelicin and psoralen.

Psoralens are natural furocoumarins well-known for their photosensitizing potential. Porphyrins, including hematoporphyrin derivatives (HPD), are also potent photosensitizers. ... Psoralens ... have an action spectrum in the UV-A range. /Psoralens/