7H-Furo[3,2-g][1]benzopyran-7-on

Psoralen was detected in the urine of three participants 2-3 hours after consumption of grapefruit and/or grapefruit juice but was not detected in the urine prior to consumption; reported concentrations over a 24-hour period were 0.0, 0.0, 0.29, 18.41, 6.38, 21.83, 20.35, 4.97, and 3.31 ng/mg after 0-1h, 1-2h, 2-3h, 3-4h, 4-5h, 5-10h, 10-15h, 15-20h, and 20-24h, respectively; psoralen was not detected in the grapefruit or the juice that was consumed suggesting this compound is a metabolite of other furocoumarins in grapefruit(1).

BACKGROUND: The use of psoralen-UVA (PUVA) in patients of skin phototype I to II is limited by side effects of acute phototoxicity and possible long-term carcinogenesis. OBJECTIVE: We sought to assess oral Polypodium leucotomos (PL) extract in decreasing PUVA-induced phototoxicity of human skin on a clinical and histologic level. METHODS: A total of 10 healthy patients with skin phototypes II to III were exposed to PUVA alone (using 0.6 mg/kg oral 8-methoxypsoralen) and to PUVA with 7.5 mg/kg of oral PL. RESULTS: Clinically, phototoxicity was always lower in PL-treated skin after 48 to 72 hours (P<0.005), and pigmentation was also reduced 4 months later. Histologically, PL-treated skin showed a significant numeric reduction of sunburn cells (P=0.05), preservation of Langerhans cells (P< or =0.01), decrease of tryptase-positive mast cell infiltration (P<0.05), and decrease of vasodilation (P< or =0.01). No differences were found in Ki-67+ proliferating cells. CONCLUSIONS: PL is an effective chemophotoprotector against PUVA-induced skin phototoxicity and leads to substantial benefits of skin protection against damaging effects of PUVA as evidenced by histology.

Chemotherapy is the recommended treatment for advanced-stage cancers. However, the emergence of multidrug resistance (MDR), the ability of cancer cells to become simultaneously resistant to different drugs, limits the efficacy of chemotherapy. Previous studies have shown that herbal medicine or natural food may be feasible for various cancers as potent chemopreventive drug. This study aims to explore the capablility of reversing the multidrug resistance of docetaxel (DOC)-resistant A549 cells (A549/D16) of psoralen and the underlying mechanisms. In this study, results showed that the cell viability of A549/D16 subline is decreased when treated with psoralen plus DOC, while psoralen has no effect on the cell proliferation on A549 and A549/D16 cells. Furthermore, mRNA and proteins levels of ABCB1 were decreased in the presence of psoralen, while decreased ABCB1 activity was also revealed by flow cytometry. Based on these results, we believe that psoralen may be feasible for reversing the multidrug resistance by inhibiting ABCB1 gene and protein expression. Such inhibition will lead to a decrease in ABCB1 activity and anti-cancer drug efflux, which eventually result in drug resistance reversal and therefore, sensitizing drug-resistant cells to death in combination with chemotherapeutic drugs.

Furanocoumarin compound psoralen (PRN) is a major active ingredient found in herbaceous plants. PRN has been used for the treatment of various dermal diseases in China. We evaluated the inhibitory effect of PRN on cytochrome P450 2B6 (CYP2B6) and found that PRN induced a time-, concentration-, and NADPH-dependent inactivation of CYP2B6 with the values of KI and kinact being 110.2 uM and 0.200 min(-1), respectively. Ticlopidine, a CYP2B6 substrate, prevented the enzyme from the inactivation induced by PRN. Exogenous nucleophile glutathione (GSH) and catalase/superoxide dismutase showed limited protection of CYP2B6 from the inactivation. The estimated partition ratio of the inactivation was approximately 400. GSH trapping experiments indicates that an epoxide or/and gamma-ketoenal intermediate was formed in microsomal incubations with PRN. In summary, PRN was characterized as a mechanism-based inactivator of CYP2B6.

Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC(50), k(inact), and K(I) values were 10.4 +/- 1.4 uM, 0.060 +/- 0.002 min(-1), and 1.13 +/- 0.12 uM for PRN, and 7.1 +/- 0.6 uM, 0.10 +/- 0.01 min(-1), and 1.95 +/- 0.31 uM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC(50) values of 0.26 +/- 0.01 uM and 0.22 +/- 0.03 uM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 +/- 0.002 min(-1) and 0.40 +/- 0.06 uM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.

For more Interactions (Complete) data for Psoralen (40 total), please visit the HSDB record page.

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.

In open label trials, serum ALT or AST elevations occurred in 2% to 12% of subjects treated with methoxsalen and UV light. The elevations were usually mild-to-moderate in severity, asymptomatic and self-limited in course. Clinically apparent acute liver injury has also been reported with oral methoxsalen therapy, but only in isolated case reports including one instance attributed to topical methoxsalen therapy. The time to onset has ranged from 1 to 5 months, the typical latency being 6 to 8 weeks. The onset is generally insidious, with appearance of nausea and abdominal pain followed by jaundice. Fever occurs in some cases, but rash and eosinophilia are not common. The typical pattern of injury is hepatocellular. Most published cases of psoralen hepatotoxicity have been mild-to-moderate in severity, but severe jaundice and death from hepatic failure has been described in patients with preexisting cirrhosis who developed further acute liver injury attributed to methoxsalen. Most cases resolve within 6 to 8 weeks.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 61(SRC), determined from a log Kow of 1.67(2) and a regression-derived equation(3), indicates that psoralen is expected to have high mobility in soil(SRC). Volatilization of psoralen 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). Psoralen is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.4X10-6 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 61(SRC), determined from a log Kow of 1.67(2) and a regression-derived equation(3), indicates that psoralen 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 a year, respectively(SRC). According to a classification scheme(5), an estimated BCF of 6(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), psoralen, which has an estimated vapor pressure of 5.4X10-6 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 psoralen 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) derived using a structure estimation method(2). Vapor-phase psoralen 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(3). Particulate-phase psoralen may be removed from the air by wet and dry deposition(SRC). Psoralen contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

IDENTIFICATION AND USE: Psoralen is a solid. Psoralen photochemotherapy (PUVA) is the combined treatment of skin disorders with a photosensitizing drug (Psoralen) and UltraViolet A radiation. The introduction of PUVA therapy has arguably been the most important development in dermatology over the past 30 years. HUMAN STUDIES: Exposure to more than 350 PUVA treatments greatly increases the risk of squamous cell carcinoma. Exposure to fewer than 150 PUVA treatments has, at most, modest effects on squamous cell carcinoma risk. Even high-dose exposure to PUVA does not greatly increase basal cell carcinomaa risk. The risks of squamous cell carcinom in long-term PUVA-treated patients should be considered in determining the risk of this therapy relative to other treatments for severe psoriasis. Psoralen ultraviolet B radiation (PUVB) can contribute to blue vitiligo. Psoralen can generate a very unique type of DNA damage, namely ICL (interstrand cross-link). An ICL can severely block DNA replication and transcription and cause programmed cell death. It is proposed that PUVA therapy conditions are more favorable for the formation of immunosuppressive rather than membrane-damaging psoralen photooxidation products. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen upregulated cyclin E1 and p27 protein levels in these cells. ANIMAL STUDIES: Mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 hr after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. In addition, psoralen upregulated cyclin E1 and p27 protein levels in mouse livers. In rats, the liver was the target of toxicity of psoralen. Multivariate analysis identified 7 metabolites in serum samples and 15 in liver samples as potential biomarkers in liver injury induced by psoralen. In addition, psoralen can cause a disturbance in amino acid metabolism, especially valine, leucine, and isoleucine biosynthesis in both serum and liver samples. Mutagenic activity of psoralen was studied in the HGPRT system on V79 Chinese hamster cells in culture. When activated by near-ultraviolet (NUV) light, were effective in inducing HGPRT mutants. Albino guinea pigs were treated with furocoumarin derivatives plus 320-400 NM UV radiation, and DNA was extracted from their epidermis. The electron microscopic assay was sensitive enough to put an upper limit of 1 crosslink/10X6 nucleotide pairs (80 cross-links/chromosome) for the low dose studies. Psoralen was demonstrated to exhibit in vitro inhibitory actions on monoamine oxidase (MAO) activities in rat brain mitochondria, preferentially inhibiting MAO-A activity over MAO-B activity. ECOTOXICITY STUDIES: The rRNA genes from fungi, plants, and animals give distinctly bimodal distributions of psoralen crosslinking, which has led to the suggestion that these genes might be largely devoid of nucleosomes when transcriptionally active. Chromatin structure of the multicopy rRNA and histone genes was studied during sea urchin early embryogenesis. The rRNA genes, which are weakly expressed, give a unimodal distribution of weak psoralen crosslinking, in contrast to the situation in all other organisms studied. The early histone genes were more accessible to psoralen crosslinking when active than inactive.

The Koc of psoralen is estimated as 61(SRC), using a log Kow of 1.67(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that psoralen is expected to have high mobility in soil(SRC).

Psoralen is a naturally occurring furocoumarin in several plants including Rutaceae sp. such as bergamot, limes and cloves, Umbelliferae sp. such as celery and parsnips, Leguminosae for example Psoralan coryfolia, and Moraceae sp. such as figs(1).

/HUMAN EXPOSURE STUDIES/ BACKGROUND: Ultraviolet (UV) radiation therapies are commonly used to treat a wide range of dermatological conditions. However, no published data exist regarding the rate of acute adverse events occurring within the different UV therapy modalities. AIM: The aim of this study was to determine the rate of acute adverse events experienced by patients receiving narrow-band UVB or photochemotherapy in 3 neighboring dermatology units. METHOD: Standardized adverse event forms from all 3 units were retrospectively analyzed over a 12-month period between October 2003 and September 2004. The treatments included were narrow-band UVB and systemic, bath and hand/foot PUVA. RESULTS: A total of 8784 treatments were given over the study period. The total number of acute adverse events recorded for all phototherapy treatments was 70 (0.8%). The rates of acute adverse events for each treatment modality were 0.6% for narrow-band UVB, 1.3% for systemic PUVA, 1.3% for bath PUVA and 0.8% for hand/foot PUVA. Adverse events were due to patient non-compliance with standard operating procedures in 15 cases (21%) and operator error in 2 (3%). Only 4 of the acute adverse events were considered to be severe, accounting for 0.05% of all treatments. CONCLUSIONS: The rates of acute adverse events with phototherapy in this analysis were low, in particular the rate of severe adverse events. The highest rate was seen with both systemic and bath PUVA. The number of adverse events resulting from operator error was low. These published rates for adverse events associated with narrow-band UVB and PUVA may help other units when analyzing their own rate of adverse events.

/HUMAN EXPOSURE STUDIES/ BACKGROUND: The use of psoralen-UVA (PUVA) in patients of skin phototype I to II is limited by side effects of acute phototoxicity and possible long-term carcinogenesis. OBJECTIVE: We sought to assess oral Polypodium leucotomos (PL) extract in decreasing PUVA-induced phototoxicity of human skin on a clinical and histologic level. METHODS: A total of 10 healthy patients with skin phototypes II to III were exposed to PUVA alone (using 0.6 mg/kg oral 8-methoxypsoralen) and to PUVA with 7.5 mg/kg of oral PL. RESULTS: Clinically, phototoxicity was always lower in PL-treated skin after 48 to 72 hours (P<0.005), and pigmentation was also reduced 4 months later. Histologically, PL-treated skin showed a significant numeric reduction of sunburn cells (P=0.05), preservation of Langerhans cells (P< or =0.01), decrease of tryptase-positive mast cell infiltration (P<0.05), and decrease of vasodilation (P< or =0.01). No differences were found in Ki-67+ proliferating cells. CONCLUSIONS: PL is an effective chemophotoprotector against PUVA-induced skin phototoxicity and leads to substantial benefits of skin protection against damaging effects of PUVA as evidenced by histology.

/HUMAN EXPOSURE STUDIES/ Psoriasis patients exposed to high cumulative doses of psoralen + ultraviolet A frequently exhibit so-called "psoralen + ultraviolet A keratoses" (i.e., hyperkeratotic lesions with varying degrees of histologic atypia). The exact causes and molecular mechanisms of psoralen + ultraviolet A keratoses however, are not clear. We therefore performed DNA mutational analysis of the tumor suppressor gene p53 (exons in psoralen + ultraviolet A keratoses from 10 long-term psoralen + ultraviolet A-treated psoriasis patients. We detected 39 p53 mutations in 16 of 28 psoralen + ultraviolet A keratoses (57%) and 18 Ha-ras mutations in 11 of 25 psoralen + ultraviolet A keratoses (44%). Of the 39 p53 mutations and 18 Ha-ras mutations, 22 (56%) and 13 (72%), respectively, were of the ultraviolet fingerprint type (C-->T or CC-->TT transitions at dipyrimidine sites); 13 (33%) and two (11%), respectively, occurred at potential psoralen-binding sites (5'-TpA, 5'-TpG, or 5'-TpT DNA sequences) and were potentially psoralen + ultraviolet A induced; two (5%) and three (17%), respectively, were of ambiguous origin (ultraviolet and/or psoralen + ultraviolet A); and two (5%) and none (0%), respectively, were of the "other" type, respectively. We conclude that (1) the frequent mutation of p53 and Ha-ras may play a key part in the formation of at least some psoralen + ultraviolet A keratoses; (2) environmental and/or therapeutic ultraviolet exposure may be a major cause of psoralen + ultraviolet A keratosis as most Ha-ras and p53 mutations are induced by ultraviolet light; and (3) psoralen + ultraviolet A itself plays a smaller, though direct, role in causing these mutations.