Sphondin

216.192

216.19

DTXSID20197481

White powder

48.7

2.2

1.4±0.1 g/cm3

189-191 °C

203.6±28.7 °C

1.635

In water, 5.37X10+2 mg/L at 25 °C (est)

3.8X10-6 mm Hg at 25 °C (est)

Henry's Law constant: 4.0X10-8 atm-cu m/mol at 25 °C (est)

139.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant: 1.06X10-10 cu cm/molec-sec at 25 °C (est)|Ozone reaction rate constant: 1.06X10-10 cu cm/molec-sec at 25 °C (est)

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

IDENTIFICATION AND USE: Sphondin is a component of Heracleum maximum roots, these roots are commonly used by the indigenous peoples of North America for the treatment of respiratory ailments including tuberculosis. HUMAN STUDIES: Photoepicutaneous testing showed weak phototoxic effects from sphondin. Photocontact allergy to psoralens in Heracleum laciniatum occurred in two persons volunteering for investigations into phototoxicity of plant homogenates and purified psoralens. Photoallergy was noted following the fifth exposure in case 1, and the sixth in case 2. Testing with diluted solutions demonstrated allergy to sphondin, isobergapten and pimpinellin. ANIMAL STUDIES: Sphondin effectively inhibited mouse coumarin 7-hydroxylase (COH) activity. Sphondin showed anti-proliferative activity and caused G2/M arrest at concentrations of 0.05-15.0 uM when tested against B16F10 melanoma cells.

At concentrations up to 6.7 ppm, 8-methoxypsoralen, sphondin, and khellin are not toxic to first-instar larvae of the mosquito Aedes aegypti. The irradiation of sensitized larvae with long-wavelength ultraviolet light did not always produce any immediate toxicity enhancement, but delayed effects were clearly visible. These were observed over the development of the organisms from first-instar larvae to adults. No adverse effects were noted when larvae were irradiated in the absence of sensitizers, or when they were placed in solutions of sensitizers which had been previously irradiated with the same light sources. 8-Methoxypsoralen was slightly more phototoxic than its isomer sphondin. Khellin, recently reported to undergo photoinduced cyclization with DNA components, showed minimal phototoxicity in the concentration range used.

Sphondin has been found in some plants in the Apiaceae family (e.g. parsnip)(1).|ETHNOPHARMACOLOGICAL RELEVANCE: Heracleum maximum is amongst the most commonly used plants by the indigenous peoples of North America. The First Nations of the eastern Canada use infusions of Heracleum maximum roots for the treatment of respiratory ailments including tuberculosis. Previous investigations of extracts derived from the roots of Heracleum maximum have shown it to possess antimycobacterial activity. AIM OF THE STUDY: To isolate and identify antimycobacterial constituents from the roots of Heracleum maximum. MATERIALS AND METHODS: A methanolic extract of Heracleum maximum roots was subjected to bioassay guided fractionation using the microplate resazurin assay (MRA) to assess inhibitory activity against Mycobacterium tuberculosis strain H37Ra. The antimycobacterial constituents were identified by NMR, MS and polarimetry. RESULTS: The polyacetylene (3R,8S)-falcarindiol and the furanocoumarins bergapten, isobergapten, angelicin, sphondin, pimpinellin, isopimpinellin and 6-isopentenyloxyisobergapten were isolated from the Heracleum maximum root extract. (3R,8S)-Falcarindiol and 6-isopentenyloxyisobergapten exhibited MICs of 24 uM and 167 uM and IC50s of 6 uM and 27 uM against Mycobacterium tuberculosis H37Ra respectively. The remaining furanocoumarins bergapten, isobergapten, angelicin, sphondin, pimpinellin, and isopimpinellin were less active, with MICs /median inhibatory concentrations/ of 925, 1850, 2149, 1859, 812 and 1625 uM and IC50s of 125, 344, 350, 351, 389 and 406 uM. CONCLUSIONS: (3R,8S)-Falcarindiol, bergapten, isobergapten, angelicin, sphondin, pimpinellin, isopimpinellin and 6-isopentenyloxyisobergapten were identified as the principal constituents responsible for the antimycobacterial activity of the roots of Heracleum maximum. This work supports the ethnopharmacological use of Heracleum maximum by Canadian First Nations and Native American communities as a treatment for infectious diseases, specifically tuberculosis. /Heracleum maximum/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 480(SRC), determined from a structure estimation method(2), indicates that sphondin is expected to have moderate mobility in soil(SRC). Volatilization of sphondin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.0X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Sphondin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-6 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 480(SRC), determined from a structure estimation method(2), indicates that sphondin 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 4.0X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Sphondin 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 12(SRC), from an estimated log Kow of 2.14(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), sphondin, which has an estimated vapor pressure of 3.8X10-6 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 sphondin 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 3.6 hours(SRC), calculated from its rate constant of 1.1X10-10 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 sphondin 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 sphondin may be removed from the air by wet and dry deposition(SRC). Sphondin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of sphondin with photochemically-produced hydroxyl radicals has been estimated as 1.1X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3.6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of sphondin 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(1). This corresponds to an atmospheric half-life of about 13 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). The lactone ring in analogous isopsoralen is susceptible to alkaline hydrolysis(3); therefore, sphondin may undergo hydrolysis under alkaline environmental conditions(SRC). Sphondin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 12 was calculated in fish for sphondin(SRC), using an estimated log Kow of 2.14(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).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of sphondin can be estimated to be 480(SRC). According to a classification scheme(2), this estimated Koc value suggests that sphondin is expected to have moderate mobility in soil(SRC).

The Henry's Law constant for sphondin is estimated as 4.0X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that sphondin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Sphondin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-6 mm Hg(SRC), determined from a fragment constant method(1).

Occupational exposure may be limited to dermal exposure where plants that contain sphondin are harvested or processed. The general population may be exposed to sphondin via ingestion of herbal remedies containing sphondin. (SRC)

Papilio glaucus (tiger swallowtail) is a generalist that rarely encounters plants containing furanocoumarins yet is constitutively capable of metabolizing low levels of these highly toxic allelochemicals. In larvae of this species, metabolism of linear (xanthotoxin, bergapten), and angular (angelicin, sphondin), furanocoumarins can be induced up to 30-fold by the presence of xanthotoxin in their diet. Degenerate primers corresponding to conserved amino acid sequences in three insect P450s, Musca domestica (CYP6A1), Drosophila melanogaster (CYP6A2) and Papilio polyxenes (CYP6B1), were used to clone xanthotoxin-induced P450 transcripts from P. glaucus larvae by a reverse transcription-polymerase chain reaction (RT-PCR) strategy. Positive clones encoding the highly conserved F--G-R-C-G P450 signature motif were used to isolate a full-length CYP6B4v1 cDNA from a P. glaucus xanthotoxin-induced cDNA library. Sequence comparisons indicate the P. glaucus CYP6B4v1 protein sequence is 63% and 61% identical, respectively, to the P. polyxenes furanocoumarin-inducible CYP6B1v1 and CYP6B3v1 proteins. Northern analysis indicates that CYP6B4 and related transcripts are highly induced in response to xanthotoxin. Baculovirus-mediated expression of the CYP6B4v1 protein in lepidopteran cell lines demonstrates that this P450 isozyme metabolizes isopimpinellin, imperatorin, and bergapten at high rates, xanthotoxin and psoralen at intermediate rates and angelicin, sphondin, and trioxsalen only at very low rates.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Investigations on light reactions in a patient with vitiligo are presented. The minimal erythema dose (MED) in the UVB area was approximately 1/3 of that in persons of skin type II. The application of furocoumarins (psoralens) increased light tolerance by 1 MED at 300-310 nm. Action spectrum studies with furocoumarins from Heracleum laciniatum showed the following order of potency: bergapten, pimpinellin, angelicin and sphondin. The efficacy was highest at 325-350 nm, with maxima at 330-335 nm. Pimpinellin was recently found to be phototoxic, but an action spectrum of sphondin is reported for the first time.|/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.|/CASE REPORTS/ Photocontact allergy to psoralens in Heracleum laciniatum occurred in two persons volunteering for investigations into phototoxicity of plant homogenates and purified psoralens. Photoallergy was noted following the fifth exposure in case 1, and the sixth in case 2. Testing with diluted solutions demonstrated allergy to sphondin, isobergapten and pimpinellin.|/ALTERNATIVE and IN VITRO TESTS/ Coumarin is 7-hydroxylated by the P450 isoform Cyp2a-5 in mice and CYP2A6 in humans. Various drugs, endogenous substances, plant substances and carcinogens, altogether about 90 chemicals, were evaluated as possible inhibitors of coumarin 7-hydroxylase (COH) activity in mouse microsomes. The effects of selected compounds on COH activity in human liver microsomes were also tested. The furanocoumarin derivatives methoxsalen (8-methoxypsoralen) and psoralen proved to be the most potent inhibitors of mouse COH activity (IC50 values 1.0 and 3.1 uM, respectively). The furanocoumarins bergapten (5-methoxypsoralen), isopimpinellin (5,8-dimethoxypsoralen), imperatorin and sphondin also effectively inhibited mouse COH activity (IC50 values 19-40 uM). Methoxsalen, isopimpinellin and metyrapone were also inhibitors in mice in vivo. Methoxsalen was a potent inhibitor of COH activity also in human liver microsomes, (IC50 value 5.4 uM), whereas bergapten, isopimpinellin and imperatorin had no effect. The imidazole antimycotic miconazole was a potent but non-specific inhibitor of COH activity. Several known substrates and inhibitors of members in the CYP1A, CYP2B, CYP2C, CYP2D and CYP3A subfamilies were poor inhibitors of COH activity. These results suggest that (i) the coumarin-type compounds in particular interact with the active sites of Cyp2a-5 and CYP2A6, and (ii) the active sites of Cyp2a-5 and CYP2A6 are structurally different, since a number of compounds inhibited mouse, but not human COH activity.

sphondin

Sphondin is a component of Heracleum maximum roots, these roots are commonly used by the indigenous peoples of North America for the treatment of respiratory ailments including tuberculosis.