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... 1 Furocoumarins and psoralens are 2 such phototoxic agents that can cause this reaction, 1 and these organic chemical compounds are found in many plant species consumed by humans. 2 In certain species of edible plants, specifically the Rutaceae and Umbelliferae families, the synthesis of furocoumarins from psoralen precursors is necessary for predator defense or as a stress response. 2 However, the consumption of various fruits and herbs from these families may lead to cutaneous contact with these phototoxic agents. 2 Rutaceous plants with these agents include oranges, lemons, limes, and grapefruit; umbelliferous plants with these agents include carrots, celery, parsley, and parsnips. ...
... 1 Furocoumarins and psoralens are 2 such phototoxic agents that can cause this reaction, 1 and these organic chemical compounds are found in many plant species consumed by humans. 2 In certain species of edible plants, specifically the Rutaceae and Umbelliferae families, the synthesis of furocoumarins from psoralen precursors is necessary for predator defense or as a stress response. 2 However, the consumption of various fruits and herbs from these families may lead to cutaneous contact with these phototoxic agents. 2 Rutaceous plants with these agents include oranges, lemons, limes, and grapefruit; umbelliferous plants with these agents include carrots, celery, parsley, and parsnips. 2 Following contact exposure to such foods and ultraviolet radiation exposure via direct sunlight, phytophotodermatitis can occur. ...
... 2 However, the consumption of various fruits and herbs from these families may lead to cutaneous contact with these phototoxic agents. 2 Rutaceous plants with these agents include oranges, lemons, limes, and grapefruit; umbelliferous plants with these agents include carrots, celery, parsley, and parsnips. 2 Following contact exposure to such foods and ultraviolet radiation exposure via direct sunlight, phytophotodermatitis can occur. ...
Article
Phytophotodermatitis is a cutaneous reaction caused by direct contact with phototoxic agents and subsequent sunlight exposure. Furocoumarins and psoralens are 2 phototoxic agents that can cause this reaction, and these organic chemical compounds are found in many plant species consumed by humans. Following contact exposure to such foods and ultraviolet radiation exposure via direct sunlight, phytophotodermatitis can occur. Due to the etiology of these rashes relating closely to the outdoor consumption of margaritas, the rash may be known by patients as "margarita burn." There is a classically described sequence of rash progression: erythematous macules or patches, which later become vesicles and seem similar to second-degree burns, followed by an asymptomatic hyperpigmentation. This case presents a 26-year-old female diagnosed with phytophotodermatitis following use of citrus fruits for margaritas while outdoors in direct sunlight. The diagnosis of phytophotodermatitis is often made clinically but can be complicated due to its similarity in appearance to many other common cutaneous reactions. In this patient, the differential diagnosis included solar erythema, contact dermatitis (type IV hypersensitivity reaction), polymorphic light eruption, or drug-related photosensitivity. Careful history taking is essential in not only narrowing down the differential diagnosis but also in avoiding unnecessary tests or ineffective treatments.
... Furocoumarins are a class of secondary metabolites found in various plant species world-wide [1,2]. High furocoumarin contents have been found in the Apiaceae family such as celery, parsnip, and parsley or in the Rutaceae including all citrus fruits [2]. ...
... Structurally, linear psoralens (furan moiety fused at C6 and C7, respectively) and non-linear angelicins (furan moiety fused at C7 and C8, respectively) may be differentiated. Purposefully, furocoumarins protect plants from attacks by fungi, bacteria, and herbivores [1]. In 1834, the first furocoumarin was isolated from bergamot oil but the chemical structure remained unknown for a century. ...
... Nowadays, they are used in phototherapy to treat skin diseases such as vitiligo or psoriasis due to their photo-reactivity under UV light irradiation at 320-380 nm [4,6]. However, skin contact with furocoumarins in the presence of UV light can lead to sunburn-like skin injuries with heavy blisters and edema (photodermatitis) due to their phototoxic properties [1,7]. Also, photo-activated furocoumarins may form reactive oxygen species (ROS) that may penetrate epidermal and dermal endothelial cells and damage organelles and membranes. ...
Article
The effect of furocoumarins on terpene photo-oxidation under UV-A light was investigated. For this purpose, four furocoumarins (8-methoxypsoralen, bergapten, bergaptol, bergamottin) each at a level of 5%, was added to solutions of the terpenes β-pinene, R-(+)-limonene and γ-terpinene in ethanol followed by UV irradiation at 366 nm. Bergaptol and bergamottin were synthesized and fully elucidated by NMR spectroscopy. UV-induced transformation of all terpenes was substantially reduced in the presence of furocoumarins. Best photo-protection was observed for γ-terpinene with the addition of bergaptol, i.e. degradation was reduced by 73% compared to the neat substance over a time period of ten days. Bergamottin (50.2%), bergapten (39.8%) and 8-methoxypsoralen (39.6%) also reduced degradation substantially. The protective effect of bergaptol was even noticeable at low concentrations of 0.1%. The main oxidation product of γ-terpinene was p-cymene. Limonene and β-pinene showed a predominated hydroperoxide formation under UV light which could almost completely prevented in the presence of furocoumarins. The protective effect of furocoumarins was presumably due to energy dissipation as a result of the conversion of high energetic radiation (UV-A) into visible light via fluorescence. Phosphorescence or self-quenching within the triplet state were further mechanisms avoiding reactions of excited furocoumarins with the terpenes under investigation. Hence, the photo-stability of the furocoumarins themselves correlated with the extent of their protective effect on all three terpenes.
... From a chemotaxonomical standpoint, furanocoumarins have been isolated from few genera within a limited group of plant families, including Apiaceae, Fabaceae, Moraceae, and Rutaceae and, to a minor degree, Amaranthaceae, Asteraceae, Cyperaceae, Meliaceae, Pittosporaceae, Rosaceae and Solanaceae [14,15]. Apiaceae and Rutaceae provide the larger number of species and the most valuable sources of furanocoumarins for pharmacological and toxicological purposes. ...
... In recent years, the innovative Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) approach has been applied for the extraction of furanocoumarins from C. × paradisi juice and food for analytical purposes [14,89,90]. After homogenization of the sample (in the case of food), acetonitrile (ACN) is added together with the QuEChERS powder, consisting of 4 g of magnesium sulfate and 1 g of sodium acetate and the internal standard. ...
... After homogenization of the sample (in the case of food), acetonitrile (ACN) is added together with the QuEChERS powder, consisting of 4 g of magnesium sulfate and 1 g of sodium acetate and the internal standard. After mixing for 1 to 5 min, the organic layer is collected and submitted directly to HPLC analysis [14,89] or to a purification step on a dispersive solid phase extraction (dSPE) tube [90]. ...
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The aim of this work is to provide a critical review of plant furanocoumarins from different points of view, including their chemistry and biosynthetic pathways to their extraction, analysis, and synthesis, to the main biological activities found for these active compounds, in order to highlight their potential within pharmaceutical science. The limits and the possible improvements needed for research involving these molecules are also highlighted and discussed.
... Vegans and vegetarians often consume vegetables containing furocumarins (i.e., celery, parsnip, carrot, parsley, citrus and figs), natural photosensitizers and triggers for phytophotodermatitis in both humans and animals [12][13][14][15][16][17][18]. Furocumarins are characterized by a coumarin structure with a furan ring and are traditionally classified into linear ("psoralen type") and angular ("angelicin type") types [19]. Furocumarins are well absorbed from food sources and rapidly distributed into several tissues, including skin [19], so phototoxic reactions due to the ingestion of food containing such photosensitizers can occur [20]. ...
... Furocumarins are characterized by a coumarin structure with a furan ring and are traditionally classified into linear ("psoralen type") and angular ("angelicin type") types [19]. Furocumarins are well absorbed from food sources and rapidly distributed into several tissues, including skin [19], so phototoxic reactions due to the ingestion of food containing such photosensitizers can occur [20]. ...
... MED was calculated more than 6 hours after the last meal to prevent furocumarins absorption peak [19]. ...
Article
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Vegans and vegetarians often consume foods containing photosensitizers capable of triggering phytophotodermatitis. The potential effect of vegan and vegetarian diets on the response of psoriatic patients undergoing phototherapy is not well characterized. We assessed clinical outcomes of vegan, vegetarian and omnivore adult psoriatic patients undergoing band ultraviolet B phototherapy (NB-UVB). In this multicenter prospective observational study, we enrolled 119 adult, psoriatic patients, of whom 40 were omnivores, 41 were vegetarians and 38 were vegans, with phototherapy indication. After determining the minimum erythemal dose (MED), we performed NB-UVB sessions for 8 weeks. The first irradiation dosage was 70.00% of the MED, then increased by 20.00% (no erythema) or by 10.00% (presence of erythema) until a maximum single dose of 3 J/cm2 was reached and constantly maintained. All the enrolled patients completed the 8 weeks of therapy. Severe erythema was present in 16 (42.11%) vegans, 7 (17.07%) vegetarians and 4 (10.00%) omnivores (p < 0.01). MED was lowest among vegans (21.18 ± 4.85 J/m2), followed by vegetarians (28.90 ± 6.66 J/m2) and omnivores (33.63 ± 4.53 J/m2, p < 0.01). Patients with severe erythema were more likely to have a high furocumarin intake (OR 5.67, 95% CI 3.74–8.61, p < 0.01). Vegans consumed the highest amount of furocumarin-rich foods. A model examining erythema, adjusted for gender, age, skin type, MED, phototherapy type, number of phototherapies and furocumarin intake, confirmed that vegans had a lower number of treatments. Vegans had more frequent severe erythema from NB-UVB, even after adjustment of the phototherapy protocol for their lower MED. Assessing diet information and adapting the protocol for vegan patients may be prudent.
... Highest furocoumarin concentrations were found in microbially infected parsnip with concentrations up to 3 g/kg [10]. Hence, furocoumarins have also been used as natural pesticides in agricultural industry to protect crops from microbial contamination [11]. In human health studies, furocoumarins proved to have antioxidant, anti-inflammatory, and bone health promoting properties [3]. ...
... In human health studies, furocoumarins proved to have antioxidant, anti-inflammatory, and bone health promoting properties [3]. In addition, furocoumarins have also been used for the treatment of skin diseases, such as vitiligo and psoriasis in a therapy called PUVA (psoralen + UV-A) [11]. However, in most cases, furocoumarins have been associated with negative physiological effects as they may act as photo-sensitizers. ...
... However, in most cases, furocoumarins have been associated with negative physiological effects as they may act as photo-sensitizers. This means that contact with furocoumarins and exposure to UV light may lead to sunburn like skin injuries called phytophotodermatitis. Photo-activated furocoumarins can also directly interact with the DNA to form mono-adducts with the base thymine, thus bearing also a carcinogenic potential [11]. For this reason, there are strict regulations for the use of essential oils containing furocoumarins in cosmetics. ...
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The impact of naturally occurring furocoumarins on essential agrumen oils, namely bergamot, lime and, lemon, was investigated upon exposure to UV-A light. For this purpose, the oils were initially freed from furocoumarins and coumarins by precipitation in cold hexane. Such pretreated oils, as well as samples of these oils spiked with separated furocoumarins were irradiated for up to 10 days. All essential oils devoid of furocoumarins showed a massive degradation of the predominant terpenes R-(+)-limonene and γ-terpinene. For lime and lemon essential oils 10% and 7.5% of the initial R-(+)-limonene amount was degraded within 10 days, respectively. In addition, a noticeable hydroperoxide formation was observed. For γ-terpinene, this effect was even more pronounced and in both, lime and lemon essential oil samples, the terpene was entirely converted into p-cymene after 6 days. In comparison, addition of 5% furocoumarins to the essential oils decelerated the photo degradation of R-(+)-limonene and γ-terpinene by up to one order of magnitude. The protective effect of furocoumarins, presumably due to bathochromic shifts of emitted light to less harmful longer wavelengths, also improved the olfactory quality. The results demonstrate that blends of non-volatile furocoumarins and volatile terpenes extend the shelf-life of light-sensitive agrumen oils.
... Isopimpinellin is a naturally occurring furanocoumarin group of phytochemicals, that is formed by the combination of coumarin and a furan ring [7,8]. Isopimpinellin is synthesized by the Umbelliferae (or Apiaceae) family plants. ...
... In summary, one previously undescribed coumarin (1) and fourteen known compounds (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) were isolated from PE extracts of Ruta graveolens. Their structures were determined by extensive spectroscopic analysis, including 1D, 2D NMR and HR-ESIMS, as well as by comparison with the literature data. ...
Article
Ruta graveolens L. has been widely used to treat various skin ailments, especially vitiligo. In this study, we isolated a new furanocoumarin named Rutagrarin (1) along with 14 known compounds (2–15) from the aerial parts of R. graveolens and elucidated their chemical structures via various spectroscopy. We found that compound 5 promoted melanogenesis and tyrosinase activity in B16 cells. Further investigation on underlying mechanisms revealed that compound 5 activated the transcription of microtia-related transcription factors and promoted the production of melanin in B16 cells via the Akt/GSK-3β/β-catenin pathway. Therefore, we confirmed the traditional efficacy of R. graveolens and speculated that compound 5 could be used as a natural drug to treat vitiligo.
... Furanocoumarin metabolism in the human body is a very complex issue studied intensively in many laboratories around the world. Because detailed scientific studies have appeared in the literature [41,42], only general aspects of the mechanism of absorption will be presented in this article. The bioavailability of furanocoumarins should be considered at several levels e.g. ...
... Psoralen, present in plasma, has not been detected in urine frequently. This suggests extensive metabolism of furanocoumarins in the organism, which requires more comprehensive studies [18,39,40,42,43]. ...
Article
Furanocoumarins are a class of natural compounds produced by several plants, including those consumed by humans. They have been used medicinally in eastern countries for ages. Given the growing body of evidence about their anticancer potential and observations that naturally occurring compounds potentiate the antitumor activity of chemotherapeutics, more attention is paid to elucidation of the nature of furanocoumarins and the possibility of using thereof in practice. The general mechanism by which furanocoumarins eliminate cancer cells is based on cell cycle blockage and initiation of programmed death like apoptosis or autophagy. The precise molecular mechanism of such an action depends on the chemical structure of furanocoumarins, which is based on the furan ring attached to the coumarin backbone in a linear or angular form as well as the type, location, and number of the substituents attached. The review summarizes the current evidence of the antitumor properties of linear and angular furanocoumarins with special emphasis on the molecular mechanism of elimination of cancer cells via apoptosis and autophagy. Negative aspects of the use of coumarins in anticancer therapy will be also discussed especially in the context of their phototoxicity and potential cancerogenic effect.
... Furocoumarins are a group of organic compounds produced by many plant species as a defense against certain pathogens and other predators (1). Furocoumarins are highly photoactive, and after absorbing energy from UV irradiation, can form adducts with DNA, thereby inhibiting DNA replication and cell division (2). ...
... Average furocoumarin consumption among all US adults was about 81 lg/day. Few other studies have attempted to estimate total furocoumarin intake, and these estimates have varied widely and changed over time (1). In 1991, Wagstaff estimated that individuals in the US consuming furocoumarin-containing foods consumed an average of 1300 lg of furocoumarins per day (27), approximately 16 times more than estimated in this study. ...
Article
Furocoumarins are a group of phototoxic compounds found in numerous edible plants. Data from cohort studies have suggested that consumption of certain furocoumarin-rich foods may increase skin cancer risk. However, no study has specifically tested this hypothesis by estimating furocoumarin intake and assessing its relationship with skin cancer. This study aimed to estimate average daily furocoumarin intake of US adults using the National Health and Nutrition Examination Survey (NHANES) 2003-2012 and to examine the relationship between furocoumarin intake and melanoma history. A database of the contents of seven furocoumarins in 29 popular foods was linked to dietary data in NHANES 2003-2012. Mean total intake of the selected furocoumarins among US adults was 81.4 μg/day (standard error = 5.5). A total of 75 participants reported a history of melanoma. Using non- and low consumers (<50th percentile) as a reference, and after adjusting for potential confounders, OR (with 95% confidence interval) of melanoma history for the top 10 percent, 80–90th percentiles, and 50–80th percentiles were 1.75 (0.43–7.20), 1.66 (0.39–7.16), and 0.90 (0.45–1.78), respectively. Furocoumarins are widely consumed among US adults, and a trend towards higher odds of melanoma history was observed among those with higher furocoumarin intake, although this relationship was not statistically significant.
... Further loss of acetone leads to a furan ring (16-19, 24-36, 39). The biochemical activities, dietary sources and intake, and potential health risks of furanocoumarins have been recently reviewed [40]. An alternative cyclization of the C-prenyl group can afford pyrano-coumarins (14,15). ...
... This extract showed a significant AChE inhibitory activity, with 75.6 % inhibition at a concentration of 50 µg/mL. A further bio-assay-guided fractionation showed that the fraction containing imperatorin (24), oxy-peucedanin (34), oxypeucedanin hydrate (35), oroserol (37), rivulobirin A (39), quercetin (40), and quercetin 3-O-glucuronide (44) was the most active against AChE, showing an IC 50 value of 25.2 µg/mL as well as good docking scores of its constituents [22]. ...
Article
Prangos ferulacea (L.) Lindl. (Fam. Apiaceae), an orophilous species of eastern Mediterranean and western Asia, possesses a number of biological properties that are worthy of exploitation in different fields. Phytochemical investigations revealed the presence of coumarins, prenyl-coumarins, and furano-coumarins as the main constituents of this species, as well as several flavonoids. Among prenyl-coumarins, osthol is a promising apoptotic agent quite selective toward cancer cells. In addition, the essential oils have been extensively investigated, and several chemotypes have been identified. This work reviews the literature on this species published between 1965 and 2018, describes its volatile and nonvolatile metabolites, and outlines its pharmacological effects.
... In humans, these toxins cause significant photodermatitis when skin is exposed to sunlight, leading to the development of blistered and burned skin. Furthermore, furocoumarins show mutagenic and carcinogenic activities in skin cells, and they may increase skin cancer risk [147,148]. Despite their toxic effects, some reports suggested that furocoumarins may potentially be used as therapeutic agents with anti-cancerogenic properties. ...
... Despite their toxic effects, some reports suggested that furocoumarins may potentially be used as therapeutic agents with anti-cancerogenic properties. Further studies are needed to evaluate their potential beneficial effect [148]. To date, at the EU level, no limits have been established for these furocoumarins in food yet. ...
Article
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Natural toxins include a wide range of toxic metabolites also occurring in food and products, thus representing a risk for consumer health. In the last few decades, several robust and sensitive analytical methods able to determine their occurrence in food have been developed. Liquid chromatography mass spectrometry is the most powerful tool for the simultaneous detection of these toxins due to its advantages in terms of sensitivity and selectivity. A comprehensive review on the most relevant papers on methods based on liquid chromatography mass spectrometry for the analysis of mycotoxins, alkaloids, marine toxins, glycoalkaloids, cyanogenic glycosides and furocoumarins in food is reported herein. Specifically, a literature search from 2011 to 2021 was carried out, selecting a total of 96 papers. Different approaches to sample preparation, chromatographic separation and detection mode are discussed. Particular attention is given to the analytical performance characteristics obtained in the validation process and the relevant application to real samples.
... For centuries EOs have attracted the attention of mankind for their biological properties, either as odoriferous material for religious or pagan practice, and perfumery, or for therapeutic applications, either in folk medicine, aromatherapy or pharmaceutical activities 5,6 . As potentially biologically active material, EOs sometimes contain significant quantities of toxic compounds such as methyleugenol (suspected carcinogen) 7,8 , safrole (weak hepatocarcinogen among other adverse effects), estragole (suspected carcinogen and genotoxic) [9][10][11][12][13] , furocoumarins (dermatitis inducers) 14,15 , and allergenic compounds, among others 16 . ...
... On a darker side, toxicity issues arise in the presence of furocoumarins, present in the non-volatile fraction of some Citrus EOs obtained by cold-pressure along with the EO (vide supra), and hydroperoxides, such as limonene hydroperoxide due to aging and auto-oxidation under air and light exposure 24 . Furocoumarins and hydroperoxides can induce skin disorders such as contact dermatitis and other allergenic reactions, and in worse cases exhibit photogenotoxicity for the former (Fig. 2) 14 . Furocoumarins total content should not exceed 1 ppm in cosmetic products in Europe 25 . ...
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Thirty-one samples of essential oils used both in perfumery and aromatherapy were purchased to business-to-consumers suppliers and submitted to standard gas chromatography-based analysis of their chemical composition. Their compliance with ISO AFNOR standards was checked and revealed, although ISO AFNOR ranges are relatively loose, that more than 45% of the samples analyzed failed to pass the test and more than 19% were diluted with solvents such as propylene and dipropylene glycol, triethyl citrate, or vegetal oil. Cases of non-compliance could be due to substitution or dilution with a cheaper essential oil, such as sweet orange oil, blending with selected compounds (linalool and linalyl acetate, maybe of synthetic origin), or issues of aging, harvest, or manufacturing that should be either deliberate or accidental. In some cases, natural variability could be invoked. These products are made available to the market without control and liability by resellers and could expose the public to safety issues, in addition to commercial prejudice, in sharp contrast with the ever-increasing regulations applying to the sector and the high demand of consumers for safe, controlled and traceable products in fragrances and cosmetic products.
... The absorption and metabolism of dietary furanocoumarins are well studied. Ingestion of, or dermal contact with, furanocoumarin-containing plants enable their absorption into the bloodstream (Melough et al. 2018). However, the kinetics and bioavailability of furanocoumarins can be quite variable depending on the dietary sources, as the matrix dictates dissolution, stability, gastric emptying, and intestinal absorption. ...
... Furanocoumarins could undergo extensive metabolism in the body; it was shown that the metabolism of these compounds began in the GI tract through the activity of intestinal bacteria or in the liver by cytochrome P450-dependent monooxygenases. It was suggested that 6 0 ,7 0 -dihydroxybergamottin (36) might be partially metabolized to bergaptol (28) before excretion in the urine (Melough et al. 2018). Although the exact pathways of furanocoumarin metabolism in humans have not yet been established conclusively, a few studies demonstrated that furanocoumarin metabolites were excreted in urine as hydroxylated products or in the form of glucuronides. ...
... Crosslink formation is associated with carcinogenicity [14], since DNA crosslink repair processes may generate point mutations, translocations, and deletions, leading to genetic instability [15]. Cross-linking frequently occurs with linear furocoumarins but is uncommon with angular furocoumarins [16]. ...
... In the westernized populations, the estimated average total intake of dietary furocoumarins is about 1.2-1.5 mg/d with Citrus species, such as grapefruit, being the main sources [16], while high-exposure peak values may reach 14 mg/d [17]. The major furocoumarins of grapefruit are bergaptol, bergamottin, and 6 ,7 -dihydroxy-bergamottin [18]. ...
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Furocoumarins are known for their phototoxic and potential carcinogenic effects. These types of compounds have previously been reported from fennel (Foeniculum vulgare Mill.), a widely used medicinal plant and spice; however, no reliable quantitative data are available on the occurrence of these compounds in fennel fruits. For the first time, we report a comprehensive analysis of fennel fruit samples of different origins, representing a wide range of accessions for their furocoumarin content. Psoralene, 5-methoxypsoralene (bergapten), and imperatorin contents of 33 fennel samples were analyzed using a sensitive liquid chromatography-mass spectrometry (LC-MS) method. When applied at the highest therapeutic dose described in the monograph issued by the European Medicines Agency, the furocoumarin content of the fruits ranged up to 1.22 μg/d, which is below the most restrictive recommendations. Based on our findings, fennel consumption can be considered as safe, at least based on its low furocoumarin content.
... Psoralene-type linear furocoumarins, like xanthotoxin and bergapten, show strong such photosensitizing effects, in contrast to angular furocoumarins. This toxicity is dependent on their ability to form DNA adducts under the influence of UV-A, leading to cross-links in DNA and, ultimately, resulting in a potent cytotoxicity and acute inflammation [23,24]. The treatments of psoriasis and vitiligo are pharmaceutical applications of furocoumarins. ...
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Background: Conium maculatum is known as highly toxic plant, due to piperidine alkaloids present in the aerial parts. In a first attempt, in various tap root samples, however, alkaloids could not be detected. The present study describes active compounds in the tap roots from 16 populations harvested at maturity. The compounds were extracted with dichloromethane from root pieces of single plants and analyzed by gas chromatography-mass spectrometry. Ten bioactive compounds were evaluated: five furocoumarins, two prenylated coumarins, two aliphatic C17-polyacetylenes and the phenylpropanoid elemicin. A high variability could be observed, the highest concentrations were measured for falcarindiol, xanthotoxin and isopimpinellin, the lowest for elemicin. In sum C. maculatum roots contained comparable amounts of compounds that are characteristic for Apiaceae, and also occur in vegetables as carrots, parsnip, parsley or celeriac.
... Seed pre-soaking in parsley extract as a single treatment enhanced mallow growth and the combined interaction of parsley extract with Na2SO4 augmented salt stress-induced reduction. A detailed study on phytochemical constituents of parsley revealed that its leaves contain a major class of coumarins, especially furocoumarin (Melough et al. 2018). Some earlier studies considered coumarin to be a growth stimulant, similar to indole acetic acid in its effect, but they differ in mode of action (Graña et al. 2017). ...
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Salinization of the agricultural soil, caused by natural factors or human activities, is one of the greatest challenges facing food production in the current time, as it negatively affects soil construction along with growth and yield of crops. In this study, an experiment was conducted on mallow plants (Corchorus olitorius L.) growing in pots to determine the effect of Na2SO4 stress on growth, physio-biochemical attributes, as well as antioxidative response, and the effect of parsley extract on salinity stress. Treatments consisted of 100 mM Na2SO4 and 10% parsley extract as single or combined treatments. Na2SO4 stress significantly reduced the plant growth, photosynthetic pigments, amino acids, glycinebetaine (GB), tannins, glutathione reductase (GR), ascorbic acid (AsA), and DPPH activity, while it significantly increased soluble sugars, proteins, proline, malondialdehyde (MDA), phenolics, catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), reduced glutathione (GSH), total antioxidant activity (via phosphomolybdate assay (PMA)) and reducing power activity (RPA). Pre-soaking of mallow seeds in parsley extract enhanced growth, pigments, phenolics, tannins, CAT, GST, DPPH and RPA compared to salt-stressed plants. Integrative treatments of parsley with Na2SO4 remarkably increased growth, pigments, sugars, GR, GST, DPPH and RPA of stressed plants, but these treatments declined proteins, amino acids, proline, GB, lipid peroxidation (MDA), tannins, CAT, SOD and GSH in stressed mallow plants. Moreover, priming with parsley extract restored the ionic homeostasis in salt-stressed mallow. The results of this study recommend pre-soaking of mallow seeds in parsley extract to confer mallow growth in moderate saline soils.
... Terpenes have shown a wide variety of biological activities such as antimicrobial [116], antiinflammatory [117], immunomodulatory [118], anticancer [119] activities. Table 1 shows an example of a terpene, its biological activity, the source of this compound, and some common spectroscopic and spectrometric methods used for its identification and quantification. ...
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The use of spectroscopic and spectrometric techniques to isolate, quantify, and characterize bioactive compounds from edible plants has become a common and mandatory activity in food chemistry. As technology advances, diverse methodologies are being applied more frequently, which are coupled most of the time to give the best diagnosis and information of a metabolite of interest. In this paper, we state the different approaches that have been performed by our research group to isolate, identify, and apply the different bioactive organic compounds obtained from some vegetal extracts. Through this review, we show the importance of the use of those analytical tools to evaluate the possible impact of some plants we included on diet for improving human health.
... 4−6 Due to their antibacterial and insecticidal properties, furanocoumarins are regarded as natural pesticides. 7 Irradiation of furanocoumarins by ultraviolet light causes electron transition and change to the triplet state. The triplet status is persistent in vivo and involved in energy transfer and phototoxicity. ...
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Furanocoumarins are photoactive compounds derived from secondary plant metabolites. They possess many bioactivities, including antioxidative, anticancer, insecticidal, and bactericidal activities. Here, we designed a new scheme for synthesizing 2-arylfuranocoumarin derivatives by condensation, esterification, bromination, and Wittig reaction. We found that 2-thiophenylfuranocoumarin (Iy) had excellent photosensitive activity. Three Iy concentrations (LC 25 , LC 50 , and LC 75) were used to treat the fourth instar larvae of Aedes aegypti (A. aegypti). The photoactivated toxicity, sublethal dose, mitochondrial dysfunction, oxidative stress level, intestinal barrier dysfunction, and apoptosis were studied. The results showed that Iy induced reactive oxygen species (ROS) production in midgut cells under ultraviolet light. Ultrastructural analysis demonstrated that mitochondria were damaged, and the activities of related enzymes were inhibited. Ultimately, Iy exposure led to excessive ROS production followed by the inhibition of antioxidant enzymes, including SOD, CAT, GPx, and GR, which diminished ROS elimination and escalated oxidative stress in midgut cells, aggravating the degree of oxidative damage in these cells. Histopathological changes were observed in the midgut, which led to intestinal barrier dysfunction. When the elimination of ROS was blocked and it accumulated in cells, apoptosis-related genes, including AeDronc, AeCaspase7, and AeCaspase8, were induced and activated. In addition, Iy affected the growth and development of A. aegypti at sublethal concentrations, and there was an obvious post-lethal effect. Thus, we found that Iy caused midgut damage and apoptosis in A. aegypti larvae under ultraviolet light, which preliminarily revealed the mode of action of Iy in A. aegypti.
... In the current study, we are focusing on furanocoumarin compounds which are five-membered furan ring compounds substituted to coumarin nucleus 26 . Psoralen and Angelicin are the two isomeric forms which are the precursors to other angular and linear furanocoumarins 27 . Furanocoumarins are compounds released by plants in stress conditions to combat against fungi, bacteria and insects 28 . ...
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Breast cancer is one of the biggest global dilemmas and its current therapy is to target the hormone receptors by the use of partial agonists/antagonists. Potent drugs for breast cancer treatment are Tamoxifen, Trastuzumab, Paclitaxel, etc. which show adverse effects and resistance in patients. The aim of the study has been on certain phytochemicals which has potent actions on ERα, PR, EGFR and mTOR inhibition. The current study is performed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The 3D structures of ERα, PR, EGFR and mTOR were obtained from the protein data bank and docked with 23 3D PubChem structures of furanocoumarin compounds using FlexX. Drug-likeness property was checked by applying the Lipinski’s rule of five on the furanocoumarins to evaluate anti-breast cancer activity. Antagonist and inhibition assay of ERα, EGFR and mTOR respectively has been performed using appropriate in-vitro techniques. The results confirm that Xanthotoxol has the best docking score for breast cancer followed by Bergapten, Angelicin, Psoralen and Isoimperatorin. Further, the in-vitro results also validate the molecular docking analysis. This study suggests that the selected furanocoumarins can be further investigated and evaluated for breast cancer treatment and management strategies.
... La répartition des deux isomères de furocoumarines n'est pas homogène au sein de ces différentes familles. En effet, on retrouve des furocoumarines linéaires et angulaires chez des Apiacées (Cook et al., 2017;Melough et al., 2018), chez certaines Fabacées (Tava et al., 2007) ainsi que chez quelques Moracées (Heinke et al., 2012), alors que les Rutacées n'accumulent que des furocoumarines linéaires (Dugrand et al., 2013). Les furocoumarines ont été mises en évidence dans la majorité des organes de la plante. ...
Thesis
Les plantes sont soumises durant leur vie à de nombreux stress environnementaux. Face à ces contraintes, les végétaux ont développé au cours de l'évolution différentes stratégies. La plus emblématique est la mise en place du métabolisme spécialisé, représenté par une grande diversité chimique et fonctionnelle. Bien que ce métabolisme soit de plus en plus étudié ces dernières années, de nombreuses lacunes persistes à son propos, liées notamment (i) à la complexité des modifications métabolomiques engendrées par la perception de stress, (ii) aux coûts et avantages que ces métabolites imputent à la plante les accumulant, et (iii) aux voies métaboliques menant à cette diversité de composés. Pour appréhender ces différentes problématiques, nous avons adopté une stratégie combinant des approches de phytochimie, de biologie moléculaire et de génétique. Dans un premier temps, nous avons étudié les changements métaboliques globaux engendrés par l’application de deux stress environnementaux, l’ozone et la blessure mécanique, sur une plante modèle au laboratoire, le panais, en fonction du temps. Les résultats de ces travaux nous ont permis d’identifier 40 métabolites différentiellement accumulés dans ces conditions, dont certaines furocoumarines. Par la suite, nous avons focalisé notre étude sur ces molécules en évaluant leurs profils d’accumulation, en condition de stress par blessures mécaniques, par la biais d’analyses différentielles. A partir de ces données, nous avons initié la recherche et l'identification de gènes candidats potentiellement impliqués dans cette voie à partir de plusieurs banques transcriptomiques et génomiques de panais. La fonction des gènes sélectionnés a été évalué par des approches d'expression hétérologue dans la levure. En parallèle de ces travaux, nous avons développé une stratégie destinée à mieux comprendre le coût métabolique de la synthèse de métabolites spécialisés. Pour ce faire, nous avons adapté aux furocoumarines une technique de clonage multigénique permettant de transférer dans une plante, et en une seule opération, plusieurs gènes impliqués dans la même voie de biosynthèse. Cette méthode nous a permis d'initier la génération de lignées stables ayant intégré les deux premiers gènes de la voie. Ces plantes seront comparées à des plantes sauvages et permettront ainsi d’étudier les coûts métaboliques et physiologiques de l’introduction de cette nouvelle voie de biosynthèse ainsi que ses bénéfices en termes de défense de la plante.
... Further loss of acetone leads to a furan ring (23-36) producing furanocoumarins (FCs). The biochemical activities, dietary sources and intake, and potential health risks of FCs have been recently reviewed (Melough et al., 2018). FCs can be of two types: linear FCs arising from demethylsuberosin and angular FCs arising from osthenol (2). ...
Article
Ethnopharmacological relevance The genus Ferulago, belonging to the Apiaceae family, is found mainly in the Mediterranean area, Southwest and Middle Asia, the Caucasus and North Africa. Since ancient times, species of this genus have been largely employed in traditional medicine for their biological properties such as antimicrobial, anti-inflammatory, antispasmodic, insecticidal, and anti-malaria, cholinesterase inhibition effects, etc. Aims The scope of this paper is to present a comprehensive respect review of this interesting genus including traditional uses, chemical composition of volatile and non-volatile metabolites, and in vitro and in vivo biological properties either utilizing the crude extracts or essential oils, or the single isolated compounds. Furthemore, critical considerations of the published data have been highlighted by comparing them with the results obtained from species of other genus belonging to the Apiaceae family. Materials and methods The available information on these genera was collected from scientific databases and cover from 1967 up to 2020. The following electronic databases were used: PubMed, SciFinder, Science Direct, Scopus, Web of Science and Google Scholar. The search terms used for this review included Ferulago, all the botanical names of the species, both accepted names or synonyms, essential oils, volatile components, traditional uses, activity, pharmacology, and toxicity. No limitations were set for languages. A total of 230 articles were included in the present review. Results Researches performed on either crude extracts, solvent fractions or isolated pure compounds from species of genus Ferulago showed several biological properties such as antibacterial, antifungal, antioxidant, antidiabetic, enzymatic, cytotoxic, anticancer, hepatoprotective, nephroprotective, antileishmanial, antimalarial, anticoagulant, anti-inflammatory, insecticidal, etc. activities. Phytochemical investigations of Ferulago species have revealed that coumarins are the main constituents of the genera. A large number of flavonoids, terpenoids and other metabolites were also identified. Furthermore, a complete review on the essential oil composition of all the taxa studied so far has been also included. Conclusion In the present study, we have provided scientific information and research developments on traditional uses, phytochemical profiles, biological activities and industrial practices on the Ferulago genus. The commercial use and the applications in agri-food sector of some of these species have been also considered. In fact, the various extracts and essential oils have been used as antioxidants and/or as antimicrobial agents, for the stabilization of sunflower and soybean oil, for food packagings, as antioxidants of mayonnaise and yogurt during their storage and, also, as economically valid source for obtaining single compounds, more expensive at a synthetic level.
... Our data suggest that both bergapten and methoxsalen prevent diabetic osteoporosis by suppressing bone resorption. be absorbed rapidly in the gastrointestinal tract [11,12]. They are metabolized mainly via cytochrome P450-dependent monooxygenase in the liver and transformed by epoxidation, hydroxylation, glucuronide conjugation and the hydrolytic opening of the lactone ring [13,14]. ...
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This study evaluated whether bergapten and methoxsalen could prevent diabetes-induced osteoporosis and its underlying mechanism. For 10 weeks, bergapten or methoxsalen (0.02%, w/w) was applied to diabetic mice that were provided with a high-fat diet and streptozotocin. Bone mineral density (BMD) and microarchitecture quality were significantly reduced in the diabetic control group; however, both bergapten and methoxsalen reversed serum osteocalcin, bone-alkaline phosphatase and femur BMD. These coumarin derivatives significantly increased bone volume density and trabecular number, whereas they decreased the structure model index of femur tissue in diabetic mice. Conversely, tartrate-resistant acid phosphatase 5 (TRAP) staining revealed that these derivatives reduced osteoclast numbers and formation in diabetic bone tissue. Additionally, both bergapten and methoxsalen tended to downregulate the expression of osteoclast-related genes such as receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear of activated T-cells, cytoplasmic 1 (NFATc1) and TRAP in diabetic femurs, with NFATc1 and TRAP expression showing significant reductions. Our data suggest that both bergapten and methoxsalen prevent diabetic osteoporosis by suppressing bone resorption.
... Furocoumarins, compounds that differ from those abovementioned by a fused furan ring to the 1-benzopyran-2-one scaffold, and employed for the same aims as those above, exhibit phototoxicity especially when interacting with ultraviolet A (UVA) radiation, thus triggering cytotoxic and mutagenic effects. Notably, this phototoxicity is currently exploited in the so-called PUVA therapy, where "P" stands for psoralen, a linear furocoumarin [6]. Given the potentiality of essential oils, we previously evaluated the mechanisms underlying the antiproliferative effect of Citrus bergamia (bergamot) essential oil (BEO), suggesting that bergamottin (BRG) and 5-geranyloxy-7methoxycoumarin (5-G-7-MOC) played a crucial role in BEO activity towards this cell line [7]. ...
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The plant kingdom has always been a treasure trove for valuable bioactive compounds, and Citrus fruits stand out among the others. Bergamottin (BRG) and 5-geranyloxy-7-methoxycoumarin (5-G-7-MOC) are two coumarins found in different Citrus species with well-acknowledged pharmacological properties. Previously, they have been claimed to be relevant in the anti-proliferative effects exerted by bergamot essential oil (BEO) in the SH-SY5Y human neuroblastoma cells. This study was designed to verify this assumption and to assess the mechanisms underlying the anti-proliferative effect of both compounds. Our results demonstrate that BRG and 5-G-7-MOC are able to reduce the proliferation of SH-SY5Y cells, inducing apoptosis and increasing cell population in sub-G0/G1 phase. Moreover, we demonstrated the pro-oxidant activity of the two coumarins that increased reactive oxygen species and impaired mitochondrial membrane potential. From a molecular point of view, BRG and 5-G-7-MOC were able to modulate apoptosis related factors at both protein and gene levels. Lastly, we evaluated the synergistic effect of their combination, finding that the highest synergy was observed at a concentration ratio similar to that occurring in the BEO, supporting our initial hypothesis. Taken together, our results deepen the knowledge regarding the effect of BRG and 5-G-7-MOC in SH-SY5Y cells, emphasizing the relevance of their cooperation in achieving this effect.
... Coumarin derivatives, particularly furocoumarins have been isolated and identified as the predominant secondary metabolites of several Prangos species. Considering the fact that furocoumarins may possess phototoxic and carcinogenic effects (Melough et al. 2018), the assessment of qualitative and quantitative data on the furocoumarin content of these plants is of primary importance. Furthermore, the summary of phytochemical components of the genus may be useful to understand better the described bioactivities and also to provide new directions for further research. ...
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The members of the Prangos genus (Apiaceae) have been widely applied in the Iranian traditional medicine internally and externally for different purposes. The aim of this review is to summarize the ethnomedicinal and food applications of Prangos species and to gather the phytochemical and pharmacological data on this genus. Among the 129 constituents isolated from Prangos species, coumarin derivatives are the main compounds. Several papers report the compositions of essential oils obtained from different plant parts, mostly containing monoterpene and sesquiterpene hydrocarbons. Various pharmacological activities of essential oils, crude extracts or isolated compounds of the Prangos species have been observed, primarily in in vitro experiments. Antioxidant, antimicrobial, cytotoxic and anti-proliferative activities have been the most extensively studied. The efficacy and safety of Prangos plants have not been assessed in animal experiments or clinical trials. Although their furocoumarin content might be a source of adverse effects, toxic effects of Prangos species have not been reported. It can be concluded, that further preclinical and clinical data are necessary to assess the rationale and safety of the medicinal and food use of Prangos species.
... Le pomelo est un fruit riche en vitamines, minéraux, pectine et autres composés phytochimiques tels que les flavonoïdes, les limonoïdes, les coumarines et les furocoumarines. Ces fruits consommés pour la chair mais aussi pour leurs produits dérivés, présentent des bienfaits pour la santé (Hung et al. 1995 ;Melough et al. 2018). Comme les autres agrumes, ils contiennent de nombreux nutriments essentiels tels que la vitamine C, le folate, les fibres alimentaires et des minéraux, en particulier du potassium (Codoñer-Franch et Valls-Bellés 2010). ...
... Most of the furanocoumarins have been chemo-taxonomically characterized from the Apiaceae, Rutaceae, and Fabaceae families [5,6]. Oxypeucedanin (OP, C 16 H 14 O 5 , molecular weight: 286.28 g/mol, 4-[(3,3-dimethyloxiran-2-yl)methoxy]furo[3,2-g]chromen-7-one) is a linear furanocoumarin containing an epoxide ring in which, at position 5, 7H-furo[3,2g] [1]benzopyran-7-one is substituted by a [(2S)-3,3-dimethyloxiran-2-yl]methoxy group ( Figure 1) [7]. ...
Article
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The present review comprehensively gathered phytochemical, bioactivity, and pharmacokinetic reports on a linear furanocoumarin, namely oxypeucedanin. Oxypeucedanin (OP), which structurally contains an epoxide ring, has been majorly isolated from ethyl acetate-soluble partitions of several genera, particularly Angelica, Ferulago, and Prangos of the Apiaceae family; and Citrus, belonging to the Rutaceae family. The methanolic extract of Angelica dahurica roots has been analytically characterized as the richest natural OP source. This naturally occurring secondary metabolite has been described to possess potent antiproliferative, cytotoxic, anti-influenza, and antiallergic activities, as assessed in preclinical studies. In order to explore potential drug candidates, oxypeucedanin, its derivatives, and semi-synthetically optimized analogues can be considered for the complementary assessments of biological assays.
... Isopimpinellin is a naturally occurring furanocoumarin group of phytochemicals that is formed by the combination of coumarin and a furan ring [7,8]. Isopimpinellin is synthesized by the Umbelliferae (or Apiaceae) family of plants. ...
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Background Angiogenesis is the formation of new blood vessels from an existing vasculature through a series of processes such as activation, proliferation, and directed migration of endothelial cells. Angiogenesis is instrumental in the metastatic spread of tumors. Isopimpinellin, a furanocoumarin group of phytochemicals, is an anticarcinogenic agent. However, no studies have proven its antiangiogenic effects. The current study thus aimed to screen the antiangiogenic effect of isopimpinellin.Methods and resultsHuman Umblical Vein Endothelial Cell (HUVEC) as an in vitro model and zebrafish embryos as an in vivo model was used in this study. The experimental results showed that isopimpinellin effectively inhibited HUVEC proliferation, invasion, migration, and tube formation, which are the key steps in angiogenesis by markedly suppressing the expression of pro-angiogenic genes VEGF, AKT, and HIF-1α. In addition, isopimpinellin exerts its anti-angiogenic effect through the regulation of miR-15b-5p and miR-542-3p. Furthermore, in zebrafish embryos, isopimpinellin inhibited the development of intersegmental vessels (ISVs) through the significant downregulation of all pro-angiogenic genes vegf, vegfr2, survivin, angpt-1, angpt-2, and tie-2.Conclusion Collectively, these experimental findings offer novel insights into the antiangiogenic nature of isopimpinellin and open new avenues for therapeutic approaches.
... Furocoumarin derivatives are an important class of heterocyclic compounds widely presented in various natural products [1][2][3][4][5][6][7]. Numerous representatives of furocoumarins possess significant biological activity [8][9][10][11][12][13][14]. ...
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For the first time, we describe a new approach towards the synthesis of previously unknown 2-(2-(4-methoxyphenyl)-4,9-dimethyl-7-oxo-7H-furo[2,3-f]chromen-3-yl)acetic acid. The presented method is based on the multicomponent condensation of 5-hydroxy-4,7-dimethyl-2H-chromen-2-one, 4-methoxyphenylglyoxal and Meldrum’s acid. It was shown that the studied reaction proceeds in two steps including the initial interaction of starting materials in MeCN and the final formation of furylacetic acid moiety in acidic media. The structures of the obtained compound were established by 1H, 13C-NMR spectroscopy and high-resolution mass spectrometry.
Article
Flavor deterioration is a serious problem in dried carrots during storage and is frequently accompanied by water absorption and bacterial growth. To explore the underlying mechanism of flavor deterioration, relationship among water status, exogenous bacterial composition and flavor changes in dried carrots were analyzed at different water activities (aw, 0.43, 0.67, 0.76 and 0.84). Results suggested that the water molecules mobility significantly increased in the dried carrots at higher aw levels (0.67, 0.76 and 0.84), this was attributed to the raised content of bound water, rather than immobilized or free water. Consequently, this accelerated microbial growth and flavor deterioration. At aw = 0.84, the characteristic flavor compounds including 2,3-butanediol, pentanoic acid, hexanoic acid, heptanoic acid and nonanoic acid were lost. The disagreeable flavor compounds including terpenes were produced during the storage period. These were the main contributors of flavor deterioration in the dried carrots. Lactic acid bacteria, as the dominant bacteria in dried carrots during storage, were proved to be closely related to the production of o-cymene, β-pinene and β-myrcene. Moreover, the emergence of Pediococcus spp. was the major factor leading to the increase of γ-terpinene in dried carrots.
Article
Citrus products are rich sources of furocoumarins, a class of photoactive compounds. Certain furocoumarins combined with ultraviolet radiation can induce skin cancer. We examined the relationship between citrus consumption and cutaneous melanoma risk among 56,205 Caucasian postmenopausal women in the Women’s Health Initiative. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by citrus intake level. During a mean follow-up of 15.7 years, 956 incident melanoma cases were documented. In multivariable adjusted models, the HR (95% CI) for melanoma was 1.12 (0.91, 1.37) among the highest citrus consumers (1.5+ servings/day of fruit or juice) versus the lowest (<2 servings/week), 0.95 (0.76, 1.20) among the highest citrus fruit consumers (5+ servings/week) versus non-consumers, and was 1.13 (0.96, 1.32) for the highest citrus juice consumers (1+ servings/day) versus the lowest (<1 serving/week). In stratified analyses, an increased melanoma risk associated with citrus juice intake was observed among women who spent the most time outdoors in summer as adults; the HR for the highest versus lowest intake was 1.22 (1.02, 1.46) (p trend = 0.03). Further research is needed to explore the association of melanoma with citrus juices among women with high sun exposure.
Article
To date, liquid chromatography coupled to a photodiode array (PDA) detector is the main technique employed to analyse furocoumarins (FCs) in essential oils. This type of detection may lead to poor performance because of the low sensitivity and selectivity of PDA detection. In this work, the linear retention index (LRI) was used in combination with a UV‐Vis library for the identification of 35 oxygen heterocyclic compounds in Citrus essential oils, making it possible to distinguish compounds with very similar spectra. As opposed to retention time, which can significantly change with the instrument or laboratory used, LRI represents a kind of normalized relative retention time, as independent as possible from operating conditions. From a qualitative point of view, reproducibility results are provided to definitively assess the suitability of such an approach for inter‐laboratory use and for a fully automated process, even when pure and very expensive standard materials are not available, as just the LRI database and the UV‐Vis library are needed. From a quantitative point of view, calibration curves were created in pure solvent and by adding standard compounds to several blank matrices, with the aim of evaluating differences, overcoming matrix effects, achieving the correct limits of quantification, and providing the quantitative profile of real samples. The LRI system is not listed in the Commission Decision 2002/657/EC as criteria for the Full Scan UV‐Vis detection; however, its validity and applicability are here investigated and proposed for future applications, in combination with the UV‐Vis library. This research proposes two analytical approaches, represented by the use of Linear Retention Index system and the construction of calibration curves on suitable blank matrices, to overcome the low selectivity and sensitivity of PDA detection in the determination of oxygen heterocyclic compounds (35 targets) in Citrus essential oils.
Article
Furanocoumarins are a class of naturally occurring phototoxic substances widely spread throughout the Umbelliferae and Rutacea families of plants. Plant extract of these families (e.g. citrus extracts) are commonly used as ingredients in fragrances and cosmetic products. Due to their phototoxicity these substances are regulated within the European Union according to the European Regulation (EC) No. 1223/2009 on cosmetic products. The proposed analytical workflow aims to swiftly screen out and determine the amount of phototoxic furanocoumarins in natural cosmetics employing solid-phase extraction (SPE). Cosmetic samples were first extracted in methanol and subsequently diluted in 35% (v/v) methanol before being applied to solid-phase extraction. The extraction procedure allows extraction of the eight target compounds including the six marker-substances proposed by the International Fragrance Association (IFRA) from complex cosmetic samples with satisfactory recovery levels ranging from 84 to 116% with the exception of bergamottin (68-89%). HPLC-UV and ESI-MS were used for the analysis of the target compounds. Furanocoumarin quantification was performed by standard addition. The workflow was successfully validated according to the ISO 12787 international standard ("Cosmetics - Analytical methods- Validation criteria for analytical results using chromatographic techniques"). Results of the validation on standard solutions highlight a LOQ of 0.01 mg kg-1, acceptable linearity up to 1 mg/kg as well as good accuracy (Bias <15%) and precision (RSD <15%). Total furanocoumarin levels of the examined natural cosmetic products were in general in agreement with the European Regulation. However, it was shown that total levels of furanocoumarins might be significantly higher than assumed using the six proposed marker substances only.
Article
An improved synthesis for 4,4′-dimethylxanthotoxol 2,3,4,6-tetra-O-acetyl-β-D-glucoside (1) starting from resorcinol was developed. Crystallographic analysis of glucoside 1 indicated that the dihedral angles between the mean planes of the tricyclic ring system of adjacent molecules was 54.820(22)° probably due to the steric hindrance caused by the bulky O-glucoside moiety, which prevents the molecules from packing via π···π stacking between the tricyclic cores. The antifungal screening data revealed that glucoside 1 had higher inhibition than its parent compound 4,4′-dimethylxanthotoxol and azoxystrobin against Rhizoctonia solani, Pyricularia grisea, and Alternaria alternate Japanese pear pathotype, with the inhibitory rates of 75.4, 65.7 and 70.1%, respectively, at the 50 µg/mL concentration.
Chapter
A systematized survey of reviews and monographs published in 2018 on all aspects of heterocyclic chemistry is given.
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Furocoumarin (furo[3,2-c]coumarin) derivatives have been synthesized from single step, high yielding (82–92%) chemistry involving a 4-hydroxycoumarin 4 + 1 cycloaddition reaction. They are characterized by FTIR, 1H-NMR, and, for the first time, a comprehensive UV-Vis and fluorescence spectroscopy study has been carried out to determine if these compounds can serve as useful sensors. Based on the fluorescence data, the most promising furocoumarin derivative (2-(cyclohexylamino)-3-phenyl-4H-furo[3,2-c]chromen-4-one, FH), exhibits strong fluorescence (ФF = 0.48) with long fluorescence lifetime (5.6 ns) and large Stokes’ shift, suggesting FH could be used as a novel fluorescent chemosensor. FH exhibits a highly selective, sensitive and instant turn-off fluorescence response to Fe3+ over other metal ions which was attributed to a charge transfer mechanism. Selectivity was demonstrated against 13 other competing metal ions (Na+, K+, Mg2+, Ca2+, Mn2+, Fe2+, Al3+, Ni2+, Cu2+, Zn2+, Co2+, Pb2+ and Ru3+) and aqueous compatibility was demonstrated in 10% MeOH-H2O solution. The FH sensor coordinates Fe3+ in a 1:2 stoichiometry with a binding constant, Ka = 5.25 × 103 M−1. This novel sensor has a limit of detection of 1.93 µM, below that of the US environmental protection agency guidelines (5.37 µM), with a linear dynamic range of ~28 (~2–30 µM) and an R2 value of 0.9975. As an exemplar application we demonstrate the potential of this sensor for the rapid measurement of Fe3+ in mineral and tap water samples demonstrating the real-world application of FH as a “turn off” fluorescence sensor.
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The enantiomeric pure and natural (+)-Lactones (C ≤ 14) with aromas obtained from fruits and milk are considered flavoring compounds. The flavoring value is related to the lactones' ring size and chain length, which blend in varying concentrations to produce different stone-fruit flavors. The nature-identical and enantiomeric pure (+)-lactones are only produced through whole-cell biotransformation of yeast. The industrially important γ-decalactone and δ-decalactone are produced by a four-step aerobic-oxidation of ricinoleic acid (RA) following the lactonization mechanism. Recently, metabolic engineering strategies have opened up new possibilities for increasing productivity. Another strategy for increasing yield is to immobilize the RA and remove lactones from the broth regularly. Besides flavor impact, γ-, δ-, ε-, ω-lactones of the carbon chain (C8-C12), the macro-lactones and their derivatives are vital in pharmaceuticals and healthcare. These analogues are isolated from natural sources or commercially produced via biotransformation and chemical synthesis processes for medicinal use or as active pharmaceutical ingredients. The various approaches to biotransformation have been discussed in this review to generate more prospects from a commercial point of view. Finally, this work will be regarded as a magical brick capable of containing both traditional and genetic engineering technology while contributing to a wide range of commercial applications.
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Hepatotoxicity from paracetamol/acetaminophen has occasionally been reported at lower than expected doses. As herbal preparations may interact with pharmaceutical drugs the following in vitro study was undertaken to determine whether the toxic effects of paracetamol on liver cell growth in culture would be exacerbated by the addition of psoralen, a furanocoumarin compound that is present in Psoralea corylifolia, a common Chinese herb. The following study utilising a liver carcinoma cell line (HepG2) showed that Psoralea corylifolia was significantly toxic from 0.3mg/ml-5mg/ml (p<0.05), whereas paracetamol was not toxic below 50mM (p=0.0026). Interactions between previously non-toxic levels of 0.1mg/ml of Psoralea corylifolia and increasing concentrations of paracetamol (0-50mM), however, were observed, with a significant increase in toxicity compared to paracetamol alone (30% cell death vs. 72% cell death with Psoralea corylifolia). A significant synergistic interaction was observed at 40mM paracetamol with 0.1mg/ml of Psoralea (p=0.038). This study has, therefore, shown significantly increased hepatotoxicity in cell cultures exposed to paracetamol when herbal compounds containing furanocoumarins were added. Fulminant acute liver failure occurring after the ingestion of low doses of paracetamol may not, therefore, always be due to an occult idiosyncratic response to paracetamol, but instead possibly to the combined effects of paracetamol and herbal preparations. Given the widespread use of both paracetamol and herbal preparations this possibility should be considered in cases of unexplained hepatic necrosis and liver failure that present for medicolegal investigation.
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Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins' defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.
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It has been hypothesized that consumption of citrus, a group of foods particularly rich in a class of photoactive compounds known as furocoumarins, may increase the risk of malignant melanoma. However, this hypothesis has not been rigorously studied in a general sample of US men and women. This study examined the relationship between citrus intake and melanoma risk in subjects of the NIH-AARP Diet and Health Study. Among 388,467 adults, 3,894 melanoma cases were identified during a median follow-up of 15.5 years. After adjustment for relevant potential confounders, total citrus consumption was not significantly associated with melanoma risk in this cohort. Among those with higher estimated exposure to ultraviolet radiation, and among those aged 60+ years at baseline, there were significant trends toward increased melanoma risk associated with whole citrus fruit consumption (P trends = 0.01 and 0.02, respectively), but the hazard ratios of the top consumers (2+ cups per week) vs. nonconsumers were nonsignificant. Further research is needed to explore associations of citrus with melanoma risk among older adults and those with high sun exposure.
Article
DNA inter-strand crosslinks (ICLs) are dangerous lesions that can be caused by a variety of endogenous and exogenous bifunctional compounds. Because covalently linking both strands of the double helix locally disrupts DNA replication and transcription, failure to remove even a single ICL can be fatal to the cell. Thus, multiple ICL repair pathways have evolved, with the best studied being the canonical Fanconi anemia (FA) pathway. However, recent research demonstrates that different types of ICLs (e.g., backbone distorting vs. non-distorting) can be discriminated by the cell, which then mounts a specific repair response using the FA pathway or one of a variety of FA-independent ICL repair pathways. This review focuses on the latter, covering current work on the transcription-coupled, base excision, acetaldehyde-induced, and SNM1A/RecQ4 ICL repair pathways and highlighting unanswered questions in the field. Answering these questions will provide mechanistic insight into the various pathways of ICL repair and enable ICL-inducing agents to be more effectively used as chemotherapeutics.
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This review summarizes the current knowledge on lactones, a class of biologically active natural products isolated from a wide range of living organisms. Butenolide, 5,6-dihydropyran-2-one, and sesquiterpene lactones display an impressive variety of bioactivities and are the most abundant in nature. This paper provides a compilation of ring construction strategies for the synthesis of small, medium, and macrolactones and discusses their biological activities and industrial, pharmaceutical, and agrochemical applications.
Chapter
Furocoumarins represent a relevant family of heterocyclic compounds of natural origin with a wide range of biological activities. Furocoumarins are currently of great interest for medical applications, and research into these compounds is becoming increasingly intense. Although some methods of synthesis of furocoumarins have been known for a long time, in the last few years there have been considerable efforts to develop new approaches for effective preparations of this type of compound. Metal-catalyzed transformations are providing appealing methodologies to access furocoumarin scaffolds in an efficient and atom-economical manner. In this present chapter, metal-catalyzed and metal-mediated routes for the construction of both furan and pyrone rings of furocoumarins are discussed. Synthetic approaches to structurally related coumestan derivatives are also presented.
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Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of expressed lemon oil and distilled lemon oil from Citrus limon (L.) Osbeck and lime oil from Citrus aurantiifolia (Christm.) Swingle, when used as sensory additives in feed for all animal species. The use of the expressed lemon oil and its residual fraction and the use of lime oil in feed is not expected to increase the exposure to furocoumarins and methoxycoumarins and perillaldehyde of those target species that are already fed citrus by-products a relevant extent (< 10%). For companion animals and ornamental fish not normally exposed to citrus by-products, no conclusion can be drawn. For the other species and for the distilled fraction of expressed lemon oil, the FEEDAP Panel concludes that the additives under assessment are safe at the maximum proposed or at reduced use levels in complete feed. The Panel considers that the use in water for drinking is safe provided that the total daily intake of the additive does not exceed the daily amount that is considered safe when consumed via feed. No concerns for consumer safety were identified following the use of the additives at the maximum proposed use level in feed. The additives under assessment should be considered as irritants to skin and eyes and the respiratory tract and as skin sensitisers. Since expressed lemon oil and its fractions contain furocoumarins, they may cause phototoxicity. The use of the additives under the proposed conditions of use in animal feed is not expected to pose a risk for the environment. Since C. limon and C. aurantiifolia and their preparations are recognised to flavour food and its function in feed would be essentially the same as that in food, no further demonstration of efficacy is considered necessary.
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Furocoumarins are a class of photoactive compounds found in several plant species, and may be responsible for the observed association between consumption of citrus products and the risk of skin cancer. Furocoumarin contents of several foods have been reported previously, but no comprehensive database of furocoumarin content of foods is currently available. Therefore, this study aimed to determine the distribution of furocoumarins in popularly consumed foods in the U.S. Samples of three varieties of each of 29 foods known or suspected to contain furocoumarins were purchased, prepared for analysis using a solid phase extraction method, and analyzed using UPLC-MS/MS for the presence of seven major furocoumarins. Most foods measured contained more than one furocoumarin, and some contained all seven of the furocoumarins examined. Total furocoumarin concentration was greatest in fresh parsley (23215 ng/g), grapefruits (21858 ng/g), lime juice (14580 ng/g), grapefruit juice (95341 ng/g), and limes (9151 ng/g). Bergamottin was found in the greatest proportion of foods sampled (23 of 29), followed by bergapten (19 of 29) and 6'7'-dihydroxybergamottin (16 of 29). These measurements will enable more accurate estimation of dietary furocoumarin exposure, and will strengthen future epidemiological work investigating the relationships between furocoumarin intake and health outcomes.
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Furanocoumarins (FCs) are a group of related plant defense metabolites occurring in several plant families, including some species in the genus citrus, such as grapefruit and pummelo. FCs function as toxins against pathogens, insects and other plant pests and some are toxic to humans at high levels. Although the levels of FCs in grapefruits are non-toxic to humans, they inhibit the intestinal enzyme CYP3A, thus preventing degradation of medicines, such as statins, and causing dangerous overdose effects. This overdosing can cause devastating side effects, ranging from stomach bleeding to kidney problems, muscle aches and irregular heartbeats. In the present study, we utilize LC/MS to characterize the levels of FCs pathway intermediates and end products in twelve citrus cultivars, including mandarin (Citrus reticulata), orange [Citrus sinensis (L.) Osbeck], Pummelo [Citrus maxima (Burm.) Merr.], grapefruit (Citrus paradisi Macf.), and two newly selected grapefruit like varieties [(Citrus reticulate) X [Citrus maxima (Burm.) Merr]. The orange and mandarin varieties do not contain FCs or FCs precursor compounds suggesting that this biosynthetic pathway is absent or inactive in mandarins and oranges and therefore a good genetic source for null alleles to FCs biosynthesis. We report the selection and characterization of two new low FCs and seedless grapefruit-like varieties, “Aliza” and “Coocki”, developed by a cross between pummelo and mandarin. Fruits of these varieties resemble grapefruit and contain high levels of the flavanone naringin, typical of grapefruit, but contain only trace amounts of FCs (based on LCMS analysis). Based on the variability of FCs content and inheritance in citrus species, the results suggest that future development of new low-FCs grapefruit varieties is an achievable objective.
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Citrus plants are able to produce defense compounds such as coumarins and furanocoumarins to cope with herbivorous insects and pathogens. In humans, these chemical compounds are strong photosensitizers and can interact with medications, leading to the “grapefruit juice effect”. Removing coumarins and furanocoumarins from food and cosmetics imply additional costs and might alter product quality. Thus, the selection of Citrus cultivars displaying low coumarin and furanocoumarin contents constitutes a valuable alternative. In this study, we performed ultra-performance liquid chromatography coupled with mass spectrometry analyses to determine the contents of these compounds within the peel and the pulp of 61 Citrus species representative of the genetic diversity all Citrus. Generally, Citrus peel contains larger diversity and higher concentrations of coumarin/furanocoumarin than the pulp of the same fruits. According to the chemotypes found in the peel, Citrus species can be separated into 4 groups that correspond to the 4 ancestral taxa (pummelos, mandarins, citrons and papedas) and extended with their respective secondary species descendants. Three of the 4 ancestral taxa (pummelos, citrons and papedas) synthesize high amounts of these compounds, whereas mandarins appear practically devoid of them. Additionally, all ancestral taxa and their hybrids are logically organized according to the coumarin and furanocoumarin pathways described in the literature. This organization allows hypotheses to be drawn regarding the biosynthetic origin of compounds for which the biogenesis remains unresolved. Determining coumarin and furanocoumarin contents is also helpful for hypothesizing the origin of Citrus species for which the phylogeny is presently not firmly established. Finally, this work also notes favorable hybridization schemes that will lead to low coumarin and furanocoumarin contents, and we propose to select mandarins and Ichang papeda as Citrus varieties for use in creating species devoid of these toxic compounds in future breeding programs.
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Animal experiments have demonstrated the photocarcinogenic properties of furocoumarins, a group of naturally occurring chemicals that are rich in citrus products. We conducted a prospective study for citrus consumption and risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin based on data from 41,530 men in the Health Professionals Follow-up Study (1986-2010) and 63,759 women in the Nurses' Health Study (1984-2010) who were free of cancers at baseline. Over 24-26 years of follow-up, we documented 20,840 incident BCCs and 3544 incident SCCs. Compared to those who consumed citrus products less than twice per week, the pooled multivariable-adjusted hazard ratios were 1.03[95% confidence interval (95% CI): 0.99-1.08] for BCC and 1.14 (95% CI: 1.00-1.30) for SCC for those who consumed two to four times per week, 1.06 (95% CI: 1.01-1.11) for BCC and 1.15 (95% CI: 1.02-1.28) for SCC for five to six times per week, 1.11 (95% CI: 1.06-1.16) for BCC and 1.22 (95% CI: 1.08-1.37) for SCC for once to 1.4 times per day, and 1.16 (95% CI: 1.09-1.23) for BCC and 1.21 (95% Cl: 1.06-1.38) for SCC for 1.5 times per day or more (Ptrend=0.001 for BCC and 0.04 for SCC). In contrast, consumption of non-citrus fruit and juice appeared to be inversely associated with risk of BCC and SCC. Our findings support positive associations between citrus consumption and risk of cutaneous BCC and SCC in two cohorts of men and women, and call for further investigations to better understand the potential photocarcinogenesis associated with dietary intakes. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Purpose Citrus products are widely consumed foods that are rich in psoralens/ furocoumarins, a group of naturally occurring chemicals with potential photocarcinogenic properties. We prospectively evaluated the risk of cutaneous malignant melanoma associated with citrus consumption. Methods A total of 63,810 women in the Nurses' Health Study (1984-2010) and 41,622 men in the Health Professionals Follow-up Study (1986-2010) were included. Dietary information was repeated assessed every 2-4 years during the follow-up. Incident melanoma cases were identified through self-report and confirmed by pathological records. Results Over 24-26 years of follow-up, we documented 1,840 incident melanomas. After adjustment for other risk factors, the pooled multivariable hazard ratios for melanoma were 1.00 for overall citrus consumption of less than twice per week (reference), 1.10 [95% confidence interval (CI), 0.94-1.30)] for two to four times per week, 1.26 (95% CI, 1.08-1.47) for five to six times per week, 1.27 (95% CI, 1.09-1.49) for once to 1.5 times per day, and 1.36 (95% CI, 1.14-1.63) for 1.6 or more times per day (Ptrend<0.001). Among the individual citrus products, grapefruit showed the most apparent association with risk of melanoma, which was independent of other lifestyle and dietary factors. The pooled multivariable hazard ratios for melanoma comparing the extreme consumption categories of grapefruit (three times or more per week vs. never) was 1.41 (95% CI, 1.10-1.82) (Ptrend<0.001). Conclusion Citrus consumption was associated with an increased risk of cutaneous malignant melanoma in two cohorts of women and men. Nevertheless, further investigation is needed to confirm our findings and explore related health implications.
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The linear furanocoumarins psoralen, bergapten, and xanthotoxin were tested for toxicity to the beet armywormSpodoptera exigua (Hübner) under short ultraviolet (UVB) radiation. Increased dietary concentrations of each furanocoumarin significantly decreased insect larval weight, extended generation time, and induced higher mortality. Xanthotoxin was the most toxic, followed by psoralen and bergapten. Combining psoralen with bergapten, xanthotoxin, or both resulted in significantly antagonistic effects on insect mortality. The combination of bergapten and xanthotoxin, however, produced additive effects. The implications of these observations forS. exigua resistance in the wild plant accession ofApium prostratum and the enigma the findings represent for plant-insect relationships are discussed.
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Grapefruits (Citrus paradisi Macfad) contain several phytochemicals known to have health maintaining properties. Due to the consumer's interest in obtaining high levels of these phytochemicals, it is important to understand the changes in their levels by common household processing techniques. Therefore, mature Texas "Rio Red" grapefruits were processed by some of the common household processing practices such as blending, juicing, and hand squeezing techniques and analyzed for their phytochemical content by high performance liquid chromatography (HPLC). Results suggest that grapefruit juice processed by blending had significantly (P < 0.05) higher levels of flavonoids (narirutin, naringin, hesperidin, neohesperidin, didymin, and poncirin) and limonin compared to juicing and hand squeezing. No significant variation in their content was noticed in the juice processed by juicing and hand squeezing. Ascorbic acid and citric acid were significantly (P < 0.05) higher in juice processed by juicing and blending, respectively. Furthermore, hand squeezed fruit juice had significantly higher contents of dihydroxybergamottin (DHB) than juice processed by juicing and blending. Bergamottin and 5-methoxy-7 gernoxycoumarin (5-M-7-GC) were significantly higher in blended juice compared to juicing and hand squeezing. Therefore, consuming grapefruit juice processed by blending may provide higher levels of health beneficial phytochemicals such as naringin, narirutin, and poncirin. In contrast, juice processed by hand squeezing and juicing provides lower levels of limonin, bergamottin, and 5-M-7-GC. These results suggest that, processing techniques significantly influence the levels of phytochemicals and blending is a better technique for obtaining higher levels of health beneficial phytochemicals from grapefruits.
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Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions by the US Food and Drug Administration (FDA) and other regulatory agencies through the creative use of specifications, action levels, tolerances, warning labels and prohibitions. Manufacturers have also played a role by setting limits on certain substances and developing mitigation procedures for process-induced toxins. Regardless of measures taken by regulators and food producers to protect consumers from natural food toxins, consumption of small levels of these materials is unavoidable. Although the risk for toxicity due to consumption of food toxins is fairly low, there is always the possibility of toxicity due to contamination, overconsumption, allergy or an unpredictable idiosyncratic response. The purpose of this review is to provide a toxicological and regulatory overview of some of the toxins present in some commonly consumed foods, and where possible, discuss the steps that have been taken to reduce consumer exposure, many of which are possible because of the unique process of food regulation in the United States.
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A rapid and sensitive reversed-phase high performance liquid chromatographic method for the quantitation of five furanocoumarins (bergaptol, psoralen, bergapten, 6',7'-dihydroxybergamottin, and bergamottin) is developed and validated. HPLC analysis of these five furanocoumarins is performed on a reversed-phase Inertsil ODS-2 column with a particle size of 5 microm. Using only water and acetonitrile as solvents, good separation, good precision, and high accuracy are obtained for the analysis of furanocoumarin components. This method is validated and applied to analyze the composition of five furanocoumarins in four citrus fruit juices (grapefruit, pomelo I, pomelo II, and shaddock) and ten Chinese herbal medicines (Bai-Zhi, Qiang-Huo, Du-Huo, Fang-Feng, Dang-Gui, Huang-Qin, Gan-Cao, Chen-Pi, Ge-Gen, and Yin-Chen-Hao) prepared by water decoction or an alcohol infusion. Results show that four of the five furanocoumarins (but not bergapten) are detected in grapefruit, pomelo I, and pomelo II, and the highest amount of these components is found in grapefruit juice. In the ten Chinese herbal medicines, the five furanocoumarins are not detected in Ge-Gen or Yin-Chen-Hao. The remaining herbs contain various compositions and amounts of furanocoumarins. In general, Chinese herbal medicines prepared by the 40% ethanol infusion contain larger amounts of furanocoumarins than those prepared by hot water decoction.
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Objectives: Extracorporeal photo-chemotherapy (ECP, photopheresis) is an approved treatment modality for mycosis fungoides (MF). Our aim is to present our ECP data for MF. Methods: We retrospectively evaluated 50 MF patients who received ECP for clinical activity, toxicity, and response and outcome rates, and we compared these with combination therapies. Results: The overall response rate (ORR) was 42% (21/50), while the median time to response was 11months (range, 3-48months). Ten of the responders (48%) had 3 or more treatment lines prior to ECP. Eight patients (16%) had adverse events related to ECP. The overall survival (OS) of 50 patients was 72months (range, 3-211). There was no statistically significant difference in the OS in early-stage vs late-stage patients (77 vs 69months, P=0.077). The stage 3 and 4 patients received an average of 31 cycles compared to 55 cycles in stage 1 and 2 patients (P=0.006). The increased extent of ECP was not correlated with the response. Combined treatment with ECP significantly improved the OS (84months vs 62months, P=0.005). Discussion: A low frequency of side effects and improved OS observed in combination therapy makes ECP a favorable option for treating MF.
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Furocoumarins are a class of organic compounds found in a variety of vegetables and fruits. Relatively little is known about the absorption and excretion of these compounds following ingestion. The objective of this study was to identify furocoumarins in grapefruit and grapefruit juice, and observe their kinetics in blood and urine. The furocoumarins detected in grapefruit using UPLC-MS/MS were bergamottin, 6',7'-dihydroxybergamottin (6',7'-DHB), epoxybergamottin, and bergaptol. Bergamottin, 6',7'-DHB, bergaptol, and bergapten were detected in grapefruit juice. In this study of 6 males and 3 females, only bergamottin and 6',7'-DHB were detected in plasma, whereas, in urine, four distinct furocoumarin metabolites as well as bergaptol, 6',7'-DHB, 8-methoxypsoralen (8-MOP), bergamottin, and psoralen were identified. Following grapefruit ingestion, furocoumarins were detectable in plasma as early as 15 minutes, and in urine within one hour. They remained in plasma for up to 3 or more hours and in urine as late as 24 hours.
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Purpose: Melanoma is an aggressive form of skin cancer. The aim of the study was to evaluate the influence of UVA radiation and psoralens: 5-methoxypsoralen (5-MOP) or 8-methoxypsoralen (8-MOP) on melanoma cells viability. Materials and methods: The amelanotic C32 and melanotic COLO829 human melanoma cell lines were exposed to increasing concentrations of psoralens (0.1-100 μM) in the presence or absence of UVA radiation. Cell viability was evaluated by the WST-1 assay. Results: We demonstrated that 8-MOP, in contrast to 5-MOP, has no cytotoxic effect on both melanoma cell lines. Simultaneous exposure of cells to 8-MOP and UVA radiation caused significant cytotoxic response in C32 cells where the EC50 value was estimated to be 131.0 μM (UVA dose: 1.3 J/cm(2)) and 105.3 μM (UVA dose: 2.6 J/cm(2)). The cytotoxicity of 5-MOP on both C32 and COLO829 cells was significantly augmented by UVA radiation - the EC50 was estimated to be 22.7 or 7.9 μM (UVA dose: 1.3 J/cm(2)) and 24.2 or 7.0 μM (UVA dose: 2.6 J/cm(2)), respectively. Conclusions: The demonstrated high cytotoxic response after simultaneous exposure of melanoma cells to psoralens and UVA radiation in vitro suggests the usefulness of PUVA therapy to treat melanoma in vivo.
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To develop a comprehensive analytical method for photoactive furanocoumarins, grapefruit (whole, flesh, peel and juice) was extracted using QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method. Seven furanocoumarins: bergaptol, psoralen, 8-methoxypsoralen, bergapten, 60,70-dihydroxybergamottin (60,70-DHB), epoxybergamottin and bergamottin were determined in grapefruit using UPLC-MS/MS. The concentrations of furanocoumarins in the plasma and urine of six healthy young adults before and after ingestion of grapefruit or grapefruit juice were also determined. Recovery rates of furanocoumarins by QuEChERS method from matrix spike sample and laboratory calibrate sample were 125.7 ± 25.4% and 105.7 ± 6.3%, respectively. Bergamottin and 60,70-DHB were predominant compounds in grapefruit flesh, juice and plasma, while bergaptol and 60,70-DHB were major compounds detected in the urine. The results demonstrated that bergamottin and 60,70-DHB were metabolized to bergaptol. Overall, the analytical methods developed in the present study can be applied to the analysis of various furanocoumarins in plant sources and biological samples.
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The increasing tolerance to currently used fungicides and the need for environmentally friendly antimicrobial approaches have stimulated the development of novel strategies to control plant-pathogenic fungi such as antimicrobial phototreatment (APT). We investigated the in vitro APT of the plant-pathogenic fungus Colletotrichum acutatum with furocoumarins and coumarins and solar radiation. The compounds used were: furocoumarins 8-methoxypsoralen (8-MOP) and 5,8-dimethoxypsoralen (isopimpinellin), coumarins 2H-chromen-2-one (coumarin), 7-hydroxycoumarin, 5,7-dimethoxycoumarin (citropten) and a mixture (3:1) of 7-methoxycoumarin and 5,7-dimethoxycoumarin. APT of conidia with crude extracts from 'Tahiti' acid lime, red and white grapefruit were also performed. Pure compounds were tested at 50μM concentration and mixtures and extracts at 12.5mgL(-1). The C. acutatum conidia suspension with or without the compounds was exposed to solar radiation for 1h. In addition, the effects of APT on the leaves of the plant host Citrus sinensis were determined. APT with 8-MOP was the most effective treatment, killing 100% of the conidia followed by the mixture of two coumarins and isopimpinellin that killed 99% and 64% of the conidia, respectively. APT with the extracts killed from 20% to 70% of the conidia, and the extract from 'Tahiti' lime was the most effective. No damage to sweet orange leaves was observed after APT with any of the compounds or extracts.
Chapter
Citrus juices are among the richest dietary sources of health-promoting compounds. Beyond the mainstream species (such as orange, grape or lemon), a wide number of other Citrus species are grown around the world, but their composition and properties have not been fully studied. The flavonoid and furocoumarin distribution in juices from C. aurantium, C. myrtifolia and C. bergamia will be described and discussed in a critical fashion, along with the ability of selected flavonoids to activate apoptotic signal cascade and to inhibit hepatoma cells proliferation.
Chapter
Orange and grapefruit contain macronutrients, micronutrients, minerals and vitamins that have been shown to have nutritional benefits of citrus, including low sodium, high potassium, presence of folic acid and high level of vitamin C. The oral administration of the citrus juice leads to the formation of their flavanone conjugated forms and, because of the low bioavailability, any action must take place at the catalytic level. The biological effects of phytochemicals have been shown to be more diverse and involve cell-mediated responses and the modulation of various cell-signalling pathways. The inflammation process is at the root of most ailments which seems to be positively affected by fruits. The major diseases that may be initiated by an inflammation process include cardiovascular diseases (CVD), metabolic syndrome, insulin resistance and type 2 diabetes, osteoporosis, dementia and some forms of cancer. Published research has provided insights on the role of citrus in human health.
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Grapefruits grown under organic or conventional systems were analyzed for 6,7-dihydroxybergamottin (DHB) and flavanones using HPLC, and DPPH activity and ORAC using a micro-plate reader. Grapefruits harvested in November 2008 (E-1) and February 2010 (E-2) were stored at room temperature (RT) and 9 °C for four weeks. Higher levels of DHB were observed in conventional grapefruits during the second (4.7 ± 0.2 μg/g), third (1.5 ± 0.2 μg/g) and fourth (2.5 ± 0.2 μg/g) week of storage at room temperature in E2. Among flavonoids analyzed, narirutin (666.7 ± 33.9 μg/g), neohesperidin (17.5 ± 1.3 μg/g), didymin (75.5 ± 5.6 μg/g) and poncirin (130.8 ± 10.4 μg/g) levels were significantly higher (P ≤ 0.05) in organic grapefruits over conventional grapefruits at harvest and storage in E-1. Although DPPH levels were moderately correlated with grapefruit flavanone content, variability in the individual flavanone activity was pronounced, resulting in non-significant differences in antioxidant activity between organic and conventional grapefruits.
Article
Furanocoumarins are organic chemical components in grapefruit (Citrus paradisi) juice that have been shown to induce potentially deleterious drug interactions. In this study we measured seven furanocoumarins (FCs) [bergamottin, 6′,7′-dihydroxybergamottin (6,7-DHB), paradisin C, bergaptol, isoimperatorin, 5′,8′-dimethylally-loxypsoralen (5,8-DMP), and epoxybergamottin (EBM)] in fruit of three grapefruit cultivars [Foster (Fos), Low Acid Foster (LAF), and Hudson (Hud)], one pummelo (C. maxima) cultivar [Hirado Buntan (HBP)], 17 randomly selected hybrids from HBP× Hud, and 31 other triploid hybrids. Bergamotton, 6,7-DHB, and paradisin C were not detected or extremely low in HBP (0.00, 0.11, and 0.00 mg L -1) and LAF (0.40, 3.83, and 0.00 mg L -1) compared with Hud (13.03. 9.58, and 6.11 mg L -1) and Fos (6.48, 14.38, and 6.11 mg L -1). In these hybrids, 6,7-DHB, bergamottin, and paradisin C obviously cosegregated in an approximate rate of 1:1. The three FCs in eight hybrids were not detected or extremely low, like HBP, the maternal parent; those in the other nine were as high as or higher than Hud, the paternal parent. The same segregation tendency was also observed in these triploid hybrids. Based on all the cultivars and hybrids, strong correlations existed among 6,7-DHB, bergamottin, and paradisin C (coefficient up to 0.909). Such strong correlations may reflect their metabolic links in the bergamottin pathway. The 1:1 cosegregation and strong correlation among the three FCs suggested that the trait of FCs is likely controlled by one single enzymatic or regulatory gene in the pathway. The FC profiles and inheritance may lead to a genomic and breeding solution to the grapefruit FC-drug interaction issue. Selection of FC-low or FC-free seedless grapefruit cultivars is underway.
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Human skin can be rendered persistently photosensitive by topical application of aqueous 8-methoxypsoralen (8-MOP) and exposure to a suberythemogenic dose of more than 380 nm radiation. We report an action spectrum for the elicitation of phototoxic erythema induced by a second exposure of skin pretreated in this way. After correction for unsensitized skin erythema this action spectrum resembles the absorption spectrum of the 4',5'-monoadduct of 8-MOP to DNA. This suggests that the monoadduct is the chromophore for erythema elicited by the second irradiation, and supports the DNA crosslink as the crucial photoproduct causing phototoxic erythema due to 8-MOP in human skin.
Article
In the current study, we examined the effects of postharvest degreening and storage on phytochemicals in Rio Red grapefruit. Grapefruits were degreened with 3.5μl/l of ethylene at 21°C and 80% relative humidity for 72h, while non-degreened fruits were used as the control. Furthermore, the grapefruits were stored at 11°C for 3weeks and then at 21°C for 2weeks. Degreening improved the peel colour of the grapefruit without affecting total soluble solids or acidity of the juice. Degreened fruits had significantly more ascorbic acid after 35days of storage. Degreening had no significant effect on the levels of carotenoids, limonoids and flavonoids as compared to the non-degreened fruits, after 35days of storage. However, after 7days, degreened fruits had more limonin and flavonoids and less furocoumarin, namely 6',7'-dihydroxybergamottin. Overall, ethylene treatment had a significant effect on the phytochemical contents of Rio Red grapefruit, especially after 7days of storage. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Due to the furanocoumarin compounds in the fruit, the production and consumption of grapefruit have been affected in the past decades since the 'grapefruit juice effect' was declared. To provide elite germplasm and obtain knowledge for future citrus breeding programs, the contents of 4 furanocoumarin monomers (FCMs) in the juice sacs from 73 citrus germplasms were evaluated using ultra-performance liquid chromatography. 6',7'-Dihydroxybergamottin and bergamottin were dominant in all the tested grapefruits, while there were some pomelos with dominant epoxybergamottin, and some with dominant 6',7'-dihydroxybergamottin and bergamottin. The contents of FCMs were low or below detection in sweet oranges, mandarins, lemons and trifoliate oranges. The results also show that the dominant patterns of FCMs are genotype-related, and crossing and selection are effective approaches to alter FCM profiles in citrus breeding. Furthermore, the contribution of pomelo as a parent to grapefruit regarding their FCM profiles was discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Some furanocoumarins in grapefruit (Citrus paradisi) are associated with the so-called grapefruit juice effect. Previous phytochemical quantification and genetic analysis suggested that the synthesis of these furanocoumarins may be controlled by a single gene in the pathway. In this study, cDNA-amplified fragment length polymorphism (cDNA-AFLP) analysis of fruit tissues was performed to identify the candidate gene(s) likely associated with low furanocoumarin content in grapefruit. Fifteen tentative differentially expressed fragments were cloned through the cDNA-AFLP analysis of the grapefruit variety Foster and its spontaneous low-furanocoumarin mutant Low Acid Foster. Sequence analysis revealed a cDNA-AFLP fragment, Contig 6, was homologous to a substrate-proved psoralen synthase gene, CYP71A22, and was part of citrus unigenes Cit.3003 and Csi.1332, and predicted genes Ciclev10004717m in mandarin and orange1.1g041507m in sweet orange. The two predicted genes contained the highly conserved motifs at one of the substrate recognition sites of CYP71A22. Digital gene expression profile showed the unigenes were expressed only in fruit and seed. Quantitative real-time PCR also proved Contig 6 was down-regulated in Low Acid Foster. These results showed the differentially expressed Contig 6 was related to the reduced furanocoumarin levels in the mutant. The identified fragment, homologs, unigenes, and genes may facilitate further furanocoumarin genetic study and grapefruit variety improvement.
Article
This review examines the biological properties of coumarins, widely distributed at the highest levels in the fruit, followed by the roots, stems and leaves, by considering their beneficial effects in the prevention of some diseases and as anti-cancer agents. These compounds are well known photosensitizing drugs which have been used as pharmaceuticals for a broad number of therapeutic applications requiring cell division inhibitors. Despite this, even in the absence of ultraviolet rays they are active. The current paper mainly focuses on the effects of psoralens on human breast cancer as they are able to influence many aspects of cell behavior, such as cell growth, survival and apoptosis. In addition, analytical and pharmacological data have demonstrated that psoralens antagonize some metabolizing enzymes, affect estrogen receptor stability and counteract cell invasiveness as well as cancer drug resistance. The scientific findings summarized highlight the pleiotropic functions of phytochemical drugs, given that recently their target signals and how these are modified in the cells have been identified. The encouraging results in this field suggest that multiple modulating strategies based on coumarin drugs in combination with canonical chemotherapeutic agents or radiotherapy could be a useful approach to address the treatment of many types of cancer.
Article
Furocoumarins (FCs) are natural constituents widely occurring in plants used as food or in phytomedicines, cosmetics etc. Some FCs exert dermal photo-toxicity and -genotoxicity when combined with UVA irradiation. For a few congeners, skin tumor formation has been described in humans and laboratory animals. Since almost no information is available on the photo-toxic properties of several congeners, we analyzed the photo-cytotoxic, photo-mutagenic, and photo-clastogenic properties in V79 cells for thirteen naturally occurring FCs, and for the coumarin limettin. Furthermore, nine FC mixtures including one mixture based on the FC pattern of an Angelica archangelica extract were tested in the same assays. We found that the concept of relative potency factors for photo-cytotoxic, -mutagenic, and -clastogenicpotencies of FCs, setting the value for 5-methoxypsoralen at 1.00, was applicable to all congeners tested. The concept was used successfully to describe the photo-toxic properties of binary mixtures of 5- and 8-methoxypsoralen. Furthermore, the photo-genotoxic (photo-mutagenic and -clastogenic) properties of complex FC mixtures comprising up to nine different congeners could be predicted. These data suggest that FCs can differ widely in their photo-toxic and photo-genotoxic properties but show relatively strict additivity with respect to their on target-effects when occurring as complex mixtures.
Article
Grapefruit is a rich source of flavonoids but also contains furanocoumarins, which are known to strongly interact with a variety of medications. Thus, characterization of grapefruit furanocoumarin metabolites may help in a better understanding of grapefruit-drug interactions. In the present work, identification of the main metabolites of grapefruit juice furanocoumarins in urine was performed by ultraperformance liquid chromatography (UPLC) coupled to linear ion trap-Orbitrap mass spectrometry (LTQ-Orbitrap). Glucuronides of 6',7'-dihydroxybergamottin and a hydroxybergamottin-like metabolite were identified for the first time as grapefruit juice metabolites. Afterward, a fast and sensitive method based on solid-phase extraction (SPE) and UPLC coupled to triple quadrupole-tandem mass spectrometry (QqQ-MS/MS) was developed for determination of the identified metabolites in urine. The proposed method was applied to urine samples of five volunteers after intakes of moderate doses of grapefruit, lemon, and orange juices. Furanocoumarin metabolites were only detected in urines after consumption of grapefruit juice.
Article
In the current study, influence of storage temperature (11 and 2 °C) and low temperature conditioning (7 days at 16 °C before cold storage at 2 °C) on the bioactive compounds in ‘Star Ruby’ grapefruit (Citrus paradisi Macf.) were examined. Fruits stored at 11 °C showed no CI; while fruits stored at 2 °C showed highest CI. Conditioning treatment (CD) reduced the incidence of CI. Carotenoids and flavonoids were significantly higher after 16 weeks in fruits stored at 11 °C. Low temperature storage (2 °C and CD) helped to retain ascorbic acid for a longer period (12 weeks). Higher furocoumarins and taste scores along with less decay development were observed in CD fruits. Conditioning treatment can be utilized to reduce CI and to maintain taste and certain bioactive compounds of grapefruits during prolonged storage at low temperature. However, for a short storage period, 11 °C temperature is more effective.
Article
Ethnopharmacological relevance: The dried fruit of Psoralea corylifolia L. has been used to prevent and treat vitiligo, osteoporosis, arthralgia and asthma in Traditional Chinese Medicine for some 1600 years. Psoralen (P), isopsoralen (IP), psoralenoside (PO) and isopsoralenoside (IPO) are the major coumarins and coumarin-related benzofuran glycosides in Psoraleae Fructus, which have been reported to show estrogen-like activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. The first aim of this study is to develop a rapid, sensitive and selective ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach for simultaneous determination of PO, IPO, P and IP in rat plasma and samples collected from in vitro incubation experiments. The second aim is to investigate the pharmacokinetic properties of PO, IPO, P and IP after oral administration of Psoralea corylifolia extract (PCE) to rats. The third aim is to confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. Materials and methods: A UPLC-MS/MS method with a C18 column and a mobile phase of methanol-0.1% aqueous formic acid was validated according to the criteria in FDA guidelines about bioanalytical method, which was developed to investigate the pharmacokinetic behavior of PO, IPO, P and IP from PCE and the metabolic pathways of PO to P or IPO to IP. Results: The criteria for establishment of a new UPLC-MS/MS method including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect and stability were validated. This method was successfully applied to the quantitative determination of PO, IPO, P and IP in biological samples collected from both in vitro incubations and in vivo rat experiments. After oral administration of PCE to rat, pharmacokinetic parameters of these four compounds indicated that in vivo biotransformation may occur between PO and P or IPO and IP. Purified benzofuran glycosides fraction (PBGF), containing only PO and IPO, was orally administered to rats to further confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. An in vitro incubation study elucidated that PO and IPO were metabolized to P and IP by intestinal microflora through de-glucosylation. Conclusions: This paper developed a rapid, sensitive and selective UPLC-MS/MS method for simultaneous determination of PO, IPO, P and IP from PCE in biological samples, and investigated on their comprehensive in vivo and in vitro pharmacokinetic studies. These obtained results showed that the metabolism by intestinal bacteria plays an important role in pharmacological effects of orally administered PCE.
Article
A linear furocoumarin phytoalexin response was observed in stressed celery (Apium graveolens). Heretofore, linear furocoumarins found in diseased c
Article
Owing to the more frequent use of parsnips, which may contain phototoxic furocoumarins, in domestic and industrial food products, the DFG Senate Commission on Food Safety (SKLM) has studied toxicological evaluations of furocoumarins in foods and has assessed data relating to exposure, metabolism, kinetics, toxicity, carcinogenicity, reproductive and developmental toxicity, as well as the effects of these substances on xenobiotic metabolism. After reviewing the available data, the subject was discussed on September 23-24, 2004, and the following opinion was passed.
Article
The combined effects of 8-methoxypsoralen (8-MOP) and ultraviolet radiation (UVR) in a photosensitizing protocol (psoralen-UVA, PUVA) were studied in hairless albino mice. The psoralen was administered orally by a pulse-feeding technique in which fasted mice were provided access to psoralen-containing feed. The mice were then exposed to radiation sources consisting of flurorescent “blacklight” lamps (F74T12 PUVA, Sylvania) either with or without an intervening filter designed to eliminate shortwave (UVB, λ < 320 nm) radiation. Exposure intervals were selected so that the total amount of ultraviolet A (UVA, λ 320–400 nm) delivered by the two configurations was equal (2 J/cm2). A series of dietary levels of 8-MOP provided mice with 0, 100, 250, and 625 mg/kg of diet. Neither radiation source, nor any tested 8-MOP level, produced grossly evident cutaneous damage, produced carcinogenesis, or reduced survival. In combination with either source, there was a consistent dosage-dependent enhancement of carcinogenesis by 8-MOP. This response was statistically significant at the middle and high dosage levels in female mice. In male mice the same trend was observed, but enhancement was significant only at the highest 8-MOP level in combination with filtered radiation, and at the two 8-MOP levels in combination with unfiltered radiation. In both sexes, survival time was significantly decreased by combinations of the highest 8-MOP level and either radiation source. Early deaths accompanied relatively severe chronic phototoxicity. Accelerated mortality and chronic phototoxicity were first observed after several months, were progressive, and were more severe in female mice and in mice exposed to the unfiltered (UVB-containing) source. Although explicit causes of death were not established, mortality appeared to result from the cutaneous damage rather than from processes analogous to UVB-induced life shortening. The combination of orally administered 8-methoxypsoralen (not carcinogenic to skin) and UVA radiation (noncarcinogenic at the levels tested) is carcinogenic in male and female hairless mice. Exclusion of UVB from the radiation source slightly reduces but does not eliminate the carcinogenic efficacy of the combination.
Article
Abstract— The photosensitizing effects of 8-methoxypsoralen on the skin of two strains of hairless mice were studied using fractionated exposure to UV Spectral dependent differences for tumorigenesis were studied by comparing the tumor responses to three different spectra; the exposure levels for each spectrum here adjusted in proportion to their relative efficiencies for tissue damage and cytokinetic responses. There were no strain differences in the spectral dependent induction of cutaneous damage or estimates of the photomediated interstrand cross-linking of epidermal DNA by 8-methoxypsoralen. Squamous cell carcinomas were induced in the photosensitized skin of both strains of mice after fractionated exposures to emissions at principally 365 nm. Exposures to a broader spectrum of light resulted in the earlier appearance of tumors in the photosensitized skin of the SKH: hairless-1 mice, but produced few or no tumors in the HRS/J/Anl strain. In a second series of experiments; mice were exposed to a fluorescent sun lamp prior to each combined treatment of psoralen and exposure at 365 nm to determine the influence of shorter wavelengths of UV on the tumor response. These treatments resulted in an enhanced expression of tumors in the SKH:hairless-1 mice as compared to the HRS/J/Anl strain. Under the conditions of the experiments, the marked strain and spectral dependent differences for tumorigenesis demonstrated that although treatments that induce psoralen photoadducts also induce tumors. there was no apparent quantitative correlation between the occurrence of DNA cross-links and the incidence of tumors. The