Pimpinellin

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. Cause of phototoxicity in patient with vitiligo. (L579)

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 320(SRC), determined from a structure estimation method(2), indicates that pimpinellin is expected to have moderate mobility in soil(SRC). Volatilization of pimpinellin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.4X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Pimpinellin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-6 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 320(SRC), determined from a structure estimation method(2), indicates that pimpinellin 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 2.4X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Pimpinellin 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 1.70(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), pimpinellin, which has an estimated vapor pressure of 1.2X10-6 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 pimpinellin 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 hours(SRC), calculated from its rate constant of 2.1X10-10 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 pimpinellin with ozone has been estimated as 2.1X10-17 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 13 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). Particulate-phase pimpinellin may be removed from the air by wet and dry deposition(SRC). Pimpinellin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Pimpinellin is a component of Angelica dahurica roots which is a medicinal plant widely used in China for the treatment of symptoms related to allergic inflammation. HUMAN STUDIES: Photoepicutaneous testing showed phototoxic effects from pimpinellin. Action spectrum studies demonstrated peak photosensitivity in the range 330-335 nm. It inhibited growth of human carcinoma cells. Moreover, pimpinellin inhibited the growth of tumor cells via the induction of tumor cell apoptosis. ANIMAL STUDIES: Pimpinellin was phototoxic the in vitro Candida test.

Pimpinellin acts as antagonist of proteins with GABA receptor activity (L579). 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).

Pimpinellin was isolated from the roots of Angelica dahurica(1) and Toddalia asiatica (Rutaceae)(2). Pimpinellin is found in the fruits of Heracleum mantegazzianum Sommier and Levier (Apiaceae)(3). Pimpinellin was detected in the leaves of 11 species of bamboo collected from Beijing and Changning Counties, China(4). In immature seeds of parsnip (Pastinaca sativa), 10.5% of total furanocoumarin compounds was identified as pimpinellin(5).

Pimpinellin concentrations in various plants(1).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of pimpinellin can be estimated to be 320(SRC). According to a classification scheme(2), this estimated Koc value suggests that pimpinellin is expected to have moderate mobility in soil(SRC).

/HUMAN EXPOSURE STUDIES/ Isolation of the furocoumarins (psoralens) bergapten, isobergapten, sphondin, isopimpinellin and pimpinellin from the Umbilliferous plant Heracleum laciniatum was carried out by column chromatography, and the structure and absorption spectra for the 5 furocoumarins isolated are described. Photoepicutaneous testing showed the strongest phototoxic effects from bergapten, marked effects from pimpinellin, weak effects from sphondin and none from the others. These in vivo findings were confirmed by the in vitro Candida test. Action spectrum studies demonstrated peak photosensitivity in the range 330-335 nm, bergapten being more than twice as phototoxic as pimpinellin.

/ALTERNATIVE and IN VITRO TESTS/ BACKGROUND: Cyrtomium fortumei (J.) Smith is an important Chinese herbal medicine because of its biological functions. However, systematic and comprehensive studies on the phytochemicals from Cyrtomium fortumei (J.) Smith and their bioactivity are limited. RESULTS: Using the bioassay-guided technique, the ethyl acetate and n-BuOH extracts of the rhizomes of Cyrtomium fortumei (J.) Smith were shown to exhibit good antitumor activities, consequently leading to the isolation of 23 compounds. All compounds were isolated from the plant for the first time. The inhibitory activities of these compounds were investigated on tumor cells MGC-803, PC3, and A375 in vitro by MTT (thiazolyl blue tetrazolium bromide) assay, and the results showed that pimpinellin (3) had potent cytotoxic activities against the three cell lines, with the IC50 values of 14.4 +/- 0.3 uM, 20.4 +/- 0.5 uM, and 29.2 +/- 0.6 uM, respectively. The mechanism of the antitumor action indicated that pimpinellin inhibited the growth of MGC-803 cells via the induction of tumor cell apoptosis, with apoptosis ratio of 27.44% after 72 hr of treatment at 20 uM. CONCLUSIONS: This study suggests that most of the compounds from the roots of Cyrtomium fortumei (J.) Smith could inhibit the growth of human carcinoma cells. Moreover, pimpinellin inhibited the growth of tumor cells via the induction of tumor cell apoptosis.

Not listed by IARC. IARC has assessed other furocoumarins, classifying 8-methoxypsoralen as carcinogenic to humans (Group 1), 5-methoxypsoralen as possibly carcinogenic to humans (Group 2A), and certain other furocoumarins as not being classifiable as to their carcinogenicity to humans (Group 3). (L135)

An estimated BCF of 6 was calculated in fish for pimpinellin(SRC), using an estimated log Kow of 1.70(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for pimpinellin is estimated as 2.4X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that pimpinellin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Pimpinellin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-6 mm Hg(SRC), determined from a fragment constant method(1).

/ALTERNATIVE and IN VITRO TESTS/ Isolation of the furocoumarins (psoralens) bergapten, isobergapten, sphondin, isopimpinellin and pimpinellin from the Umbilliferous plant Heracleum laciniatum was carried out by column chromatography, and the structure and absorption spectra for the 5 furocoumarins isolated are described. Photoepicutaneous testing showed the strongest phototoxic effects from bergapten, marked effects from pimpinellin, weak effects from sphondin and none from the others. These in vivo findings were confirmed by the in vitro Candida test. Action spectrum studies demonstrated peak photosensitivity in the range 330-335 nm, bergapten being more than twice as phototoxic as pimpinellin.