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Furocoumarins: A review of biochemical activities, dietary sources and intake, and potential health risks
... During the last two decades, particular attention has been paid to the potential role of dietary furocoumarins in the development of CM [11]. Furocoumarins are found in many plant species that synthesize furocoumarin via the fusion of coumarin with a furan ring [12]. Different furocoumarin isomers are generated depending on the position of the furan ring. ...
... Another aspect that complicates the comparison is a circumstance that affects all exposure categories, namely that the furocoumarin content of the same food item is subject to high variability due to a variety of causes. These causes include the cultivar of a particular food, the growing conditions and geographical location, the degree of ripeness at harvest and possible post-ripening, the storage conditions, and the processing, especially heat treatment [12]. ...
... Activated by the absorption of UVR energy, furocoumarins can interact with the DNA in skin cells, which fosters the development of DNA damage and mutations. However, without UVR exposure, this reactive property remains inactive [12]. With this knowledge, it is evident that UVR exposure must be considered as an effect modifier when modeling the relationship between the consumption of furocoumarins and CM risk and not as a confounder. ...
Background/objectives:
Furocoumarins, chemical compounds found in many plant species, have a photosensitizing effect on the skin when applied topically and, by interacting with ultraviolet radiation (UVR), stimulate melanoma cells to proliferate. Whether dietary intake of furocoumarins acts as a melanoma risk factor has been investigated in several epidemiological studies, which are synthesized in our systematic review.
Methods:
The study protocol was registered with PROSPERO (registration number: CRD42023428596). We conducted an in-depth literature search in three databases coupled with forward and backward citation tracking and expert consultations to identify all epidemiological studies, irrespective of their design, addressing the association between a furocoumarin-containing diet and melanoma risk. We extracted information on the study details and results in a standardized manner and evaluated the risk of bias of the results using the Joanna Briggs Institute's critical appraisal tools.
Results:
We identified 20 publications based on 19 different studies providing information on the association between dietary furocoumarin intake and melanoma risk. We refrained from a meta-analytical synthesis of the results because of the large heterogeneity in exposure assessment, operationalization of furocoumarin intake in the analyses, and analytical methods of the studies. In a qualitative synthesis, we found moderate evidence supporting the notion that dietary furocoumarin intake at higher levels acts as a risk factor for cutaneous melanoma.
Conclusions:
Our systematic review provides an overview of the current epidemiological evidence, but it could not clearly answer whether and to what extent dietary furocoumarin intake increases melanoma risk. Future epidemiological analyses focusing on this topic require more comprehensive dietary and UVR exposure data to better characterize the individual total furocoumarin intake and its interplay with UVR exposure patterns.
... Aflatoxins are mycotoxins that are produced by naturally occurring species of fungi [1] and can be found in various foodstuff [2]. Numerous studies have been devoted to the methods for their determination and decomposition due to the serious danger they pose to human health [3][4][5][6][7][8][9][10][11][12]. Aflatoxins B 1 , B 2 , G 1 and G 2 are the most common mycotoxins and have proven highly carcinogenic effects. ...
... Furocoumarins are synthesized by plants through the fusion of a coumarin and a furan ring [13,14], generating linear or angular isomers. The two main isomers of furocoumarins are psoralens and angelicins (isopsoralens), depending on the position of the furan ring [5]. Chemical structures of psoralen and isopsoralen and aflatoxins B 1 , B 2 , G 1 and G 2 are presented on Figs. ...
... They react with their DNA thus disrupting their replication when exposed to UV light. In this way, they inhibit microbial growth and increase insect mortality [5]. The basis of all physico-chemical methods for qualitative and quantitative determination of aflatoxins is their ability to fluoresce under the influence of UV rays [5]. ...
The article presents the effects of different doses of gamma irradiation on the degradation of aflatoxins B 1 , B 2 , G 1 and G 2 in wheat flour. The experiment was conducted after contamination of wheat flour samples with mixture of aflatoxins with concentrations from 3 µg/kg to 12 µg/kg using reference material. Irradiation of flour aliquots with absorbed doses from 5.8 kGy to 27 kGy was carried out in an industrial gamma irradiation facility BULGAMMA. The concentrations of the aflatoxins before and after the radiation processing were measured by HPLC. The results showed that gamma irradiation with 27 kGy caused the highest degree of destruction of aflatoxins B 2 (82 %) and G 2 (81 %), followed by aflatoxin G 1 (65 %) and to the lowest extend of aflatoxin B 1 (59 %). Gamma irradiation with the maximum allowable dose for commercial food irradiation of 10 kGy was not sufficient to destroy the studied aflatoxins to the maximum permissible concentrations in wheat flour.
... The antibacterial qualities of essential oils like lemon and orange make them particularly wellsuited for use in products that are intended to treat skin and hair. In addition, the antibacterial qualities of these oils have created fresh opportunities for the expansion of existing businesses [26]. ...
... Lavandula angustifolia L. is indigenous to the Mediterranean region [25,26], and nowadays has worldwide distribution and represents an important commercial essential oil crop [26,27]. The main characteristic of lavender EO is its higher content in linalool/linalyl acetate and low camphor content [1,12,27,28,29]. ...
... Lavandula angustifolia L. is indigenous to the Mediterranean region [25,26], and nowadays has worldwide distribution and represents an important commercial essential oil crop [26,27]. The main characteristic of lavender EO is its higher content in linalool/linalyl acetate and low camphor content [1,12,27,28,29]. ...
When it comes to choosing which cosmetics to buy, consumers typically identify the smell as the factor that is most important to them. When uncovered, the fatty acids, oils, and surfactants that are frequently included in cosmetic formulations can all contribute to the production of odours that are unpleasant. Essential oils are used in a wide variety of cosmetic products because, in addition to the fragrant contributions they make, they serve as preservatives, active agents, and additions that are helpful to the skin. In addition, the growing demand for natural components has significantly contributed to the revival of interest in plant derivatives, particularly essential oils, in the industries of cosmetics and health. Popular cosmetic companies have been forced to promote natural fragrances and pick for minimally processed natural materials as a result of the potential health concerns related with artificial smell compounds, which are major components of cosmetics. As a result of this pressure, the cosmetic industry as a whole has moved towards natural fragrances. Some of the most highly regarded essential oils that are utilised in the creation of fragrances include citrus, lavender, eucalyptus, tea tree, and other flower oils. Some of the most highly prized scent components that are utilised in the creation of various cosmetics include linalool, geraniol, limonene, citronellol, and citral. In the fields of cosmetics and cosmeceuticals, essential oils have a wide variety of applications, including use as a source of natural fragrances. The purpose of this review was to shed light on those applications. Origins of essential oils, commercial viability of essential oils, chemical makeup of essential oils, fragrance classification, olfactory character of essential oils, authenticity, and safety will all receive the attention they deserve.
... In addition, the methanol extract showed strong antimutagenicity against 4-nitro-O-phenylenediamine, a powerful direct-acting mutagen, and 2-amino anthracene, a pro-mutagen [17]. The methanol extract also showed potent antioxidant properties on a battery of in vitro assays as well as moderate antifungal activity against Candida Furocoumarins are a class of chemical compounds with phototoxic properties found naturally in many plant species, including some commonly consumed by humans (i.e., grapefruit, carrot, parsnip, turnip, fig, lemon, lime, orange, celeriac, celery, parsley, and dill) [35]. They are synthesized by plants through the fusion of coumarin to a furan ring, generating linear or angular isomers depending on the position of the furan ring. ...
... They are synthesized by plants through the fusion of coumarin to a furan ring, generating linear or angular isomers depending on the position of the furan ring. Furocoumarins are produced by plants in response to stress and to defend against predators, such as fungi, bacteria, and insects; furocoumarins react with the DNA of these predators and disrupt replication when exposed to UV light [35]. Furocoumarins have been the focus of much research attention because of their photoactivity. ...
... Contact with furocoumarins combined with UV exposure can lead to the development of blistered and burned skin, a reaction known as phytophotodermatitis. However, both the ingestion of and dermal contact with furocoumarin-containing plants enables the absorption of furocoumarins into the bloodstream [35]. The concentration of furanocoumarins in H. sphondylium is much lower than that of the Caucasian hogweeds (H. ...
Heracleum sphondylium L., commonly known as hogweed, common hogweed, or cow parsnip, is an herbaceous plant of the Apiaceae family native to Europe and Asia. This wild edible plant is common in grasslands, herb-rich meadows, hedges, wooded areas, roadsides, and railway embankments and in both waste and cultivated grounds. This review presents both the characteristics and ethnobotany, as well as the findings, technical advances, and potential of hogweed research with the goal of improving and disseminating knowledge regarding the value and potential of this wild edible plant. Current knowledge suggests that H. sphondylium L. shows good potential as a new cash crop, being an interesting food ingredient and also a source of compounds with biological activities. Therefore, hogweed may be proposed as a new horticultural crop, although several aspects of cultivation must be examined before full domestication.
... Furanocoumarins have long served as an example of evolution of plant chemical defense (Calla et al. 2020). They are synthesized through the fusion of coumarin to a furan ring, producing linear or angular isomers depending on the position of the furan ring (Melough, Cho, and Chun 2018). The linear furanocoumarins are present in a few of plant families, while angular furanocoumarins are even more limited in distribution (Krieger et al. 2018). ...
... The linear furanocoumarins are present in a few of plant families, while angular furanocoumarins are even more limited in distribution (Krieger et al. 2018). Some furanocoumarin-containing plants, such as celery (Apiaceae) and citrus (Rutaceae) (Melough, Cho, and Chun 2018), are the hosts of H. armigera (Cunningham and Zalucki 2014). To explore whether and which CYP in the H. armigera (HarmCYP) is involved in furanocoumarin desposition, three recombinant CYP9As and four representative structure-related furanocoumarins that differ structurally in terms of the Summary • CYP9A12, CYP9A14, and CYP9A17 are capable of metabolizing psoralen and xanthotoxin. ...
Furanocoumarins are a class of chemical compounds with phototoxic properties. For herbivores, efficient detoxification of such defense compounds is the prerequisite to feed successfully on furanocoumarin-containing plants. The cotton bollworm Heli-coverpa armigera is a very important polyphagous pest in agriculture, but how it copes with toxic furanocoumarins in some of its host plants is not well understood. Given that cytochrome P450s are well known for their capacity in xenobiotic metabolism, this study attempted to explore the potential roles of cytochrome P450s in furanocoumarin transformation in this pest. Our data showed that two linear structures (psoralen and xanthotoxin) could be metabolized by three recombinant CYP9A enzymes, but no detectable depletion was observed for the linear one with the 8-dimethylallyloxy substituent on the coumarin moiety (imperatorin) and the angular furanocoumarin (angelicin). Initial epoxidation of the double bond connecting C2' and C3' of the furano ring following by cleavage of the epoxidated furan ring, leading to the formation of more soluble, less reactive and nonphotosensitizing metabolites, was identified as a common mechanism of linear furanocoumarin metabolism using a quadrupole/time-of-flight (Q-TOF) mass spectrometry interfaced with a high performance liquid chromatography (HPLC) system. Our data demonstrated that multiple P450s were involved in the detoxification of linear furanocoumarins in the cotton bollworm. These findings contribute to a better understanding of the biochemical basis of adaptation to plant defense chemicals in this economically important pest.
... Human exposure to certain coumarin derivatives in the presence of long wavelength ultraviolet light (320 to 380 nm) can result in an acute skin allergy that may persist for several months [4]. Furthermore, furocoumarins are also reported as potential photo-mutagen and photo-carcinogen [5]. Due to adverse health effects, the level of several coumarin derivatives in natural herbal products are strictly regulated in many countries. ...
... Herein, we report the development of a multiplexed liquid chromatography-mass spectrometry (LC-MS) method to analyze 25 coumarin derivatives with known or potential safety concerns [5,20]. The method development was mainly focused on the optimization of instrumental conditions and sample preparation to facilitate reliable analysis in the challenging matrix of essential oils. ...
The occurrence of coumarin-based photoactive compounds in essential oils has been a concern due to the adverse health effects it has on human health. A fit-for-purpose analytical method for major coumarin-based phototoxins is critical to guarantee the essential oils product safety and compliance with the regulatory requirements. Herein, a liquid chromatography-mass spectrometry (LC–MS) analytical method was developed to identify and quantify 25 coumarin derivatives in essential oils. The sample preparation procedure was optimized to use selective solvent extraction to remove the limonene matrix interference. To achieve the optimal sensitivity and specificity, UHPLC column of biphenyl stationary phase was used for this analysis. An inter-laboratory validation study was conducted to evaluate the method performance. The limit of quantification (LOQ) for all target analytes was validated at 5 µg/g. Satisfactory recoveries were obtained for the majority of analytes in the range of 80–115%. Both the repeatability RSDr (within-laboratory) and reproducibility RSDR (between-laboratory) were < 10%. This method was demonstrated as applicable for the quality control testing of coumarin-based phototoxins in essential oils.
... Furthermore, psoralens react with other cellular structures such as proteins or lipids. The general absorption maximum of psoralen lies between 320 nm and 400 nm, while the psoralen used in this publication has its maximum at 355 nm [16]. Dimethyl sulfoxide (DMSO, CAS: 67-85-5, purity = 99.9%, ...
... During its decay, Cherenkov light with a yield of 35 photons per decay event is produced [4]. Its physical half-life is 16 Plasmid probes with each 200 ng DNA (0.1 µg/µL) were incubated with varying volumes of chemical noxa or radionuclide solutions in 1.5 mL micro tubes (Eppendorf, Hamburg; Germany) in a total volume of 20 µL. After treating the plasmid probes, 10 µL of each DNA solution was mixed with 1.25 µL loading buffer (Invitrogen, Karlsruhe, Germany). ...
Possible enhancements of DNA damage with light of different wavelengths and ionizing radiation (Rhenium-188—a high energy beta emitter (Re-188)) on plasmid DNA and FaDu cells via psoralen were investigated. The biophysical experimental setup could also be used to investigate additional DNA damage due to photodynamic effects, resulting from Cherenkov light. Conformational changes of plasmid DNA due to DNA damage were detected and quantified by gel electrophoresis and fluorescent staining. The clonogene survival of the FaDu cells was analyzed with colony formation assays. Dimethyl sulfoxide was chosen as a chemical modulator, and Re-188 was used to evaluate the radiotoxicity and light (UVC: λ = 254 nm and UVA: λ = 366 nm) to determine the phototoxicity. Psoralen did not show chemotoxic effects on the plasmid DNA or FaDu cells. After additional treatment with light (only 366 nm—not seen with 254 nm), a concentration-dependent increase in single strand breaks (SSBs) was visible, resulting in a decrease in the survival fraction due to the photochemical activation of psoralen. Whilst UVC light was phototoxic, UVA light did not conclude in DNA strand breaks. Re-188 showed typical radiotoxic effects with SSBs, double strand breaks, and an overall reduced cell survival for both the plasmid DNA and FaDu cells. While psoralen and UVA light showed an increased toxicity on plasmid DNA and human cancer cells, Re-188, in combination with psoralen, did not provoke additional DNA damage via Cherenkov light.
... HPLC-PDA, CE-UV [44,45] 9. Coumarin Fragrance [46] Skin sensitization and eczema through dermal administration [46] 1D/2D GC-MS, UPLC-MS/MS, HPTLC, LC-MS/MS LRI [46][47][48][49] 10. Furocoumarin Fragrance [50] Phototoxicity, hyperpigmentation, erythematous rash, blisters, and sunburn if the user is exposed to UV-A radiation from the sun [51] RP-HPLC-coupled HR/AM, LC-MS, LC-MS/MS LRI [49,52,53] 11. Mercury compound Whitening agent, preservative Allergic reactions, skin irritation, or neurotoxic problems [54] ELISA ...
... Furocoumarins have a basic structure, similar to coumarins, being fused with the furan ring at the C6/C7 or C7/C8 positions, so that furocoumarins are included in the coumarin subfamily. Furocoumarin is contained in citrus essential oil, which is often used as a fragrance in cosmetics with a liquid form such as perfume [50]. ...
The general public uses cosmetics daily. Cosmetic products contain substances (ingredients) with various functions, from skincare to enhancing appearance, as well as ingredients that preserve the cosmetic products. Some cosmetic ingredients are prohibited or restricted in certain geographical regions, such as the European Union and the United States of America, due to their potential to cause adverse effects such as cancer, birth defects, and/or developmental and reproductive disorders. However, the ingredients may be used in other regions, and, hence, the monitoring of the cosmetic ingredients actually used is important to ensure the safety of cosmetic products. This review provides an overview of recent analytical methods that have been developed for detecting certain ingredients that are restricted or prohibited by the U.S. Food and Drug Administration (FDA) and/or EU legislation on cosmetic products.
... Through these mechanisms, plant furanocoumarins can ultimately disrupt the DNA replication of biological aggressors [7]. Because of their ability to interfere with DNA replication, furanocoumarins have attracted much interest for developing strategies to target malignant cells in cancer-related diseases [8]. Both angelicin-and psoralen-type structures have photosensitizing properties, although they respond differently to UV light and have different reactivity with DNA. ...
... Furocoumarins are a class of substances, which occur naturally in plants, some of which are common foods such as parsnip, celery, celeriac or citrus fruits. 1 All congeners of the substance class have in common that the basic structure is a fusion of coumarin with a furan ring, which results in linear or angular furocoumarins. 2 It depends on the particular congener how much information is available on occurrence in food and on toxicity, as summarised in recent reviews. 3 The method of choice for the determination of furocoumarins in food is liquid chromatography with mass spectrometric detection (HPLC-MS). 4 There are many older studies on the occurrence of furocoumarins in food (e.g. ...
Background
Furocoumarins are a class of substances, which naturally occur in plants and may be present in certain foods. Roughly two dozen structurally different but related substances (congeners) have been described in plants to various degrees of depth. At sufficiently high concentrations furocoumarins pose a risk to consumers' health because of their phototoxic and photogenotoxic effects. Past studies on furocoumarin content in food usually focused on a limited number of congeners or specific food types. More information on occurrence in a broad range of foods was needed.
Results
In order to improve occurrence data, the content of 23 furocoumarin congeners in 82 food samples, known to contain furocoumarins, is presented in full. A method was developed using liquid chromatography coupled to a triple quadrupole mass spectrometer. Samples ranging from soft drinks to vegetables were extracted with a methanol/water mixture. Chromatography and transitions in the MS/MS detection were optimised and all parameters are given. The furocoumarin content quantified ranged from 29 μg/kg in ginger to 98 mg/kg in lime juice. A table showing all the results of each congener in each food sample is presented. As more congeners were covered in this study than in the past, previous risk assessments were revisited, in order to determine if the risk for consumers has changed.
Conclusion
The new occurrence data determined with the newly developed method makes a valuable contribution to the available data of furocoumarins in foods. The deducible exposure data enables a review of existing risk assessments on furocoumarins. Despite the higher number of analysed furocoumarins in this study compared to other studies, the total content for each food type was only slightly different to previously published data. Therefore, conclusions of previous risk assessments were found to be still valid: Normal dietary exposure should not lead to phototoxic effects in consumers. However, due to photogenotoxic properties of certain furocoumarins, their exposure should be reduced as much as possible and some foods should be consumed in moderation.
... Additional interactions between the psoralen monoadduct and the pyrimidine base can occur during subsequent phases of UV exposure, resulting in the formation of cross-links between DNA strands. In addition, psoralens react with other cellular components, such as proteins or lipids [84]. To date, it has not been clearly established whether oxygen-dependent mechanisms are important for the induction of apoptosis in therapy. ...
Photodynamic therapy (PDT) is a minimally invasive therapeutic method with high selectivity of action. It has gained great popularity in recent years as a new therapy for the treatment of cancer, but is also used in dermatology, ophthalmology, and antimicrobial treatment, among others. The therapeutic regimen involves the administration of a photosensitizer (PS) that selectively accumulates in tumor cells or is present in the blood vessels of the tumor prior to irradiation with light at a wavelength corresponding to the absorbance of the photosensitizer, leading to the generation of reactive oxygen species (ROS). Choosing the right PS is one of the most important steps in PDT and is crucial to the effectiveness of the therapy. Despite the many compounds discovered, the search for new molecules that could fulfill the functions of an optimal photosensitizer and improve the efficiency of PDT is still ongoing. Compounds of natural origin could contribute to achieving this goal. A number of photoactive substances as effective as synthetic photosensitizers have been described in various plant and fungal species. With the increasing identification of photoactive natural products, many new photosensitizers are expected to emerge. Some have already been clinically tested with promising results. In our work, we provide insights into this research and molecules, analyze their advantages and disadvantages, and point out gaps in current knowledge and future directions for their development. We also present natural photosensitizers not yet tested in clinical trials and point out future potential directions for their development.
... , also recognized as methoxsalen, is a naturally occurring phytochemical found in numerous plant species and classified under furocoumarins [1]. Psoralen-UVA (PUVA) photochemotherapy, employing 8-MP, is commonly used for treating various pervasive skin diseases [2]. ...
This study provides a comprehensive computational exploration of the inhibitory activity and metabolic pathways of 8-methoxypsoralen (8-MP), a furocoumarin derivative used for treating various skin disorders, on cytochrome P450 (P450). Employing quantum chemical DFT calculations, molecular docking, and molecular dynamics (MD) simulations analyses, the biotransformation mechanisms and the active site binding profile of 8-MP in CYP1B1 were investigated. Three plausible inactivation mechanisms were minutely scrutinized. Further analysis explored the formation of reactive metabolites in subsequent P450 metabolic processes, including covalent adduct formation through nucleophilic addition to the epoxide, 8-MP epoxide hydrolysis, and non-CYP-catalyzed epoxide ring opening. Special attention was paid to the catalytic effect of residue Phe268 on the mechanism-based inactivation (MBI) of P450 by 8-MP. Energetic profiles and facilitating conditions revealed a slight preference for the C4′=C5′ epoxidation pathway, while recognizing a potential kinetic competition with the 8-OMe demethylation pathway due to comparable energy demands. The formation of covalent adducts via nucleophilic addition, particularly by phenylalanine, and the generation of potentially harmful reactive metabolites through autocatalyzed ring cleavage are likely to contribute significantly to P450 metabolism of 8-MP. Our findings highlight the key role of Phe268 in retaining 8-MP within the active site of CYP1B1, thereby facilitating initial oxygen addition transition states. This research offers crucial molecular-level insights that may guide the early stages of drug discovery and risk assessment related to the use of 8-MP.
... Phototherapy using furocoumarins, such as psoralen (linear furocoumarin) and angelicins and allosporalens (angular fuorocoumarins) (Fig. 1), have been extensively known and utilized (Pathak and Fitzpatrick 1992;Melough et al. 2018). The phototherapeutic activity of these compounds arises mainly from their ability to form adducts with the pyrimidine bases of DNA (Seret et al. 1992). ...
Psoralen is a family of naturally occurring photoactive compounds found in plants that acquire potential cytotoxicity when activated by specific frequencies of electromagnetic waves. Psoralens penetrate the phospholipid cellular membranes and insert themselves between the pyrimidines of deoxyribonucleic acid (DNA). Psoralens are initially biologically inert and acquire photoreactivity when exposed to certain classes of electromagnetic radiation, such as ultraviolet light. Once activated, psoralens form mono- and di-adducts with DNA, leading to marked cell apoptosis. This apoptotic effect is more pronounced in tumor cells due to their high rate of cell division. Moreover, photoactivated psoralen can inhibit tyrosine kinase signaling and influence the immunogenic properties of cells. Thus, the cytotoxicity of photoactivated psoralen holds promising clinical applications from its immunogenic properties to potential anti-cancer treatments. This narrative review aims to provide an overview of the current understanding and research on psoralen and to explore its potential future pharmacotherapeutic benefits in specific diseases.
... Reactive oxygen species can damage the nuclei, organelles, membranes, and enzymes of animal epidermal, dermal, and endothelial cells. The formation of membrane lipid peroxides, psoralen-protein adducts, and photodamage to cell membranes are suggested as additional causes of phototoxicity [81]. Furanocoumarins cause serious burns and skin damage [82,83]. ...
... Furocoumarins (FCs) are a class of natural chemical compounds that widely exists in many herbs, including some commonly used as food, cosmetics, flavorings, or herbal medicines by humans [1]. Just as its name implies, these compounds have a skeleton formed via a coumarin unit fused to a furan ring and can be divided into linear or angular isomers depending on the position of the furan ring [2]. ...
Objective: This study aimed to provide data for the type and content of linear furocoumarins (FCs) in Angelica dahurica (AD) in order to assess their cumulative risks and provide a scientific basis for the rational use and quality evaluation of the medicinal AD to improve public health. Methods: A UPLC method was developed for the simultaneous determination of nine FCs initially by using imperatorin (Im) as the internal standard substance, including Im, phellopterin (Ph), isoimperatorin (Is), oxypeucedanin hydrate (Oh), byakangelicin (Bn), xanthotoxin (8-MOP), bergapten (5-MOP), byakangelicol (Bl), and oxypeucedanin (Op) in two species of Angelica dahurica (AD). And, the risk assessment for the total FCs in AD was explored using the hazard index combined with the toxic equivalency factor (TEF-HI) strategy for the first time. Results: The established method revealed acceptable applicability, and there were no significant differences compared with the external standard method (ESM). The quantitative results demonstrated that the total content of FCs in Angelica dahurica (BZ) were higher than that in Angelica dahurica var. formosana (HBZ), and there was a great difference between the Bl and Op. Moreover, the risk assessment data revealed that the risk of total FCs in AD to human health was low. Conclusions: The established UPLC method that determined nine FCs in AD using a single marker could solve the problem of difficulty in obtaining a chemical reference substance with high purity and requiring a long determination time. And, the TEF-HI risk assessment approach associated with FCs in ADs could guide the rational utilization of toxic FCs in ADs in the progress of improving public health safety. In short, the whole systematic strategy provides a scientific basis for rational quality evaluation and the healthy use of related herbal medicines.
... Upon UV light exposure, furanocoumarins become toxic and generate photo dermatitis that produces toxicity and mutagenic disorders. They bind with cellular substrates such as lipids and proteins, leading to the generation of ROS and the formation of novel antigens by modification of the covalent bonding of proteins [49][50][51][52][53][54][55][56]. ...
Cancer is one of the main causes of death worldwide. There are several different types of cancer recognized thus far, which can be treated by different approaches including surgery, radiotherapy, chemotherapy or a combination thereof. However, these approaches have certain drawbacks and limitations. Photodynamic therapy (PDT) is regarded as an alternative noninvasive approach for cancer treatment based on the generation of toxic oxygen (known as reactive oxygen species (ROS)) at the treatment site. PDT requires photoactivation by a photosensitizer (PS) at a specific wavelength (λ) of light in the vicinity of molecular oxygen (singlet oxygen). The cell death mechanisms adopted in PDT upon PS photoactivation are necrosis, apoptosis and stimulation of the immune system. Over the past few decades, the use of natural compounds as a photoactive agent for the selective eradication of neoplastic lesions has attracted researchers’ attention. Many reviews have focused on the PS cell death mode of action and photonanomedicine approaches for PDT, while limited attention has been paid to the photoactivation of phytocompounds. Photoactivation is ever-present in nature and also found in natural plant compounds. The availability of various laser light setups can play a vital role in the discovery of photoactive phytocompounds that can be used as a natural PS. Exploring phytocompounds for their photoactive properties could reveal novel natural compounds that can be used as a PS in future pharmaceutical research. In this review, we highlight the current research regarding several photoactive phytocompound classes (furanocoumarins, alkaloids, poly-acetylenes and thiophenes, curcumins, flavonoids, anthraquinones, and natural extracts) and their photoactive potential to encourage researchers to focus on studies of natural agents and their use as a potent PS to enhance the efficiency of PDT.
... Saponins excess often causes deleterious effects such as hemolyis and permeability of the intestines [317]; and the range of toxicity of Cucurbitacins based on in vivo experiments has been found to be between 2 and 12.5 mg/kg [318]. Furocoumarins are a class of chemical compounds with phototoxic properties, and animal studies have provided evidence of the health risks associated with furocoumarins that depend on their photosensitizing properties [319]. Ernst [320] reported that evidence from various Asian countries implied that toxic heavy metals and undeclared prescription drugs in Asian herbal medicines might constitute serious health problems. ...
Background
The review aims to summarize the most important and common natural antioxidants and their resources from medicinal plants, as the vast majority in the world have always applied medicinal plants for the prevention and treatment of various diseases. Keywords were searched in PubMed/MEDLINE, Scopus, and the Institute for Scientific Information Web of Science, as well as the search engine Google Scholar.
Main body
Important traditional medicinal plants with antioxidant activities in China are Asparagus, bindii, blueberries, barberry fruit, borage, calendula, camellia, coriander, cumin, Chinese bayberry, Chinese bitter melon, Chinese cabbage, Chinese cherry, Chinese jujube, Chinese olive, pomegranate, Chinese rose tea, Chinese toon, Chinese watermelon, black tea, green tea, knotweed, Chinese quince, Chinese rhubarb, pomegranate, sumac, thyme, wolfberry, dendrobium, drumstick tree, rosemary, black Zira, rose, Fiscus species, ginger, ginkgo, goji berry, grape, Jerusalem thorn, jujube, kiwifruit seed oil, and liquorice root.
Conclusion
The main derived exogenous natural antioxidants are derived from medicinal plants, fruits, foods, flowers, and traditional herbal medicines. Among various medicinal plants, the medicinal plants common in Asian traditional medicine have shown enormous potential as great sources of natural antioxidants. Polyphenols, and some other secondary bioactive compounds like anthocyanins, isoflavones, pterostilbene, resveratol, quercetin and catechins have shown potent antioxidant activity.
... Furanocoumarin compounds are characteristic secondary metabolites of Rutaceae and Umbelliferae, and many medicinal plants, such as Angelicae Dahuricae Radix, Angelicae Pubescentis Radix, Peucedani Radix, Psoralea corylifolia Linn, and so forth, which all contain these compounds [1]. They have various pharmacological activities, mainly in anti-tumor, anti-virus, anti-oxidation, anti-inflammatory, anti-pathogenic microorganisms, and insecticidal aspects [2][3][4]. In the presence of molecular oxygen, furanocoumarin molecules transfer the energy of the excited-state triplet to the ground-state triplet oxygen to generate singlet oxygen ( 1 O 2 ), which directly attacks the biofilm target or generates free radicals and free radical anions through electron transfer, and further reacts with oxygen to produce active oxygen. ...
Furanocoumarins, the secondary metabolites of plants, are considered to be natural insecticides and fungicides because they prevent the invasion of plant pathogenic microorganisms and the predation of herbivorous insects. In this study, novel 2-arylfuranocoumarin derivatives were designed to synthesize by condensation, esterification, bromination, and Wittig reaction. The results showed an excellent photosensitive activity of 2-thiophenylfuranocoumarin (I34). Cell Counting Kit-8 detected that I34 could inhibit the proliferation of Spodoptera frugiperda (Sf9) cells in a time- and concentration-dependent manner under ultraviolet A (UV-A) light for 3 min. The inverted microscope revealed that cells treated with I34 swelled, the membrane was ruptured, and apoptotic bodies appeared. The flow cytometry detected that I34 could induce apoptosis of Sf9 cells, increase the level of intracellular reactive oxygen species (ROS), decrease the mitochondrial membrane potential, and block cell cycle arrest in the G2/M phase. Transmission electron microscopy detected cell mitochondrial cristae damage, matrix degradation, and mitochondrial vacuolation. Further enzyme activity detection revealed that the enzyme activities of apoptosis-related proteins caspase-3 and caspase-9 increased significantly (p < 0.05). Finally, Western blotting analysis detected that the phosphorylation level of Akt and Bad and the expression of the apoptosis inhibitor protein Bcl-XL were inhibited, cleaved-PARP and P53 were increased, and cytochrome C was released from the mitochondria into the cytoplasm. Moreover, under UV-A irradiation, I34 promoted the increase in ROS in Sf9 cells, activated the mitochondrial apoptotic signal transduction pathway, and finally, inhibited cell proliferation. Thus, novel furanocoumarins exhibit a potential application prospect as a biochemical pesticide.
... In fact, different in vitro and in vivo studies have also demonstrated that furanocoumarins possess positive biological activities such as anti-inflammatory and anti-oxidative activities and bone health promoting effects [58,59]. However, they can also cause undesirable effects due to interactions with certain medications or by inducing phototoxicity [60,61]. ...
Due to the high prevalence of obesity and type 2 diabetes, adipogenesis dysfunction and metabolic disorders are common features in the elderly population. Thus, the identification of novel compounds with anti-adipogenic and lipolytic effects is highly desirable to reduce diabetes complications. Plants represent an important source of bioactive compounds. To date, the antidiabetic potential of several traditional plants has been reported, among which Ficus carica L. is one of the most promising. Considering that plant metabolome changes in response to a number of factors including seasonality, the aim of this study was to evaluate whether Ficus carica leaves extracts collected in autumn (FCa) and spring (FCs) differently modulate lipid metabolism and adipogenesis in 3T3-L1 adipocytes. The 1H-NMR profile of the extracts showed that FCs have a higher content of caffeic acid derivatives, glucose, and sucrose than FCa. In contrast, FCa showed a higher concentration of malic acid and furanocoumarins, identified as psoralen and bergapten. In vitro testing showed that only FCa treatments were able to significantly decrease the lipid content (Ctrl vs. FCa 25 μg/mL, 50 μg/mL and 80 μg/mL; p < 0.05, p < 0.01 and p < 0.001, respectively). Furthermore, FCa treatments were able to downregulate the transcriptional pathway of adipogenesis and insulin sensitivity in 3T3-L1 adipocytes. In more detail, FCa 80 μg/mL significantly decreased the gene expression of PPARγ (p < 0.05), C/EBPα (p < 0.05), Leptin (p < 0.0001), adiponectin (p < 0.05) and GLUT4 (p < 0.01). In conclusion, this study further supports an in-depth investigation of F. carica leaves extracts as a promising source of active compounds useful for targeting obesity and diabetes.
Host plant selection may depend on the metabolic system in herbivorous insects. Although oligophagous insects take up specific host plant components, how host plant components and their biological activities are altered through their metabolic systems remains unknown. Here, by examining gene expression of metabolic enzymes and components in the larval frass, we investigated the metabolic ability of Papilio memnon larvae fed with Citrus x paradisi (grapefruit) against host plant components. The gene expression levels of some metabolic enzymes were fluctuated between the larval midgut and the larval fat bodies. Furthermore, the chloroform extract from the larval frass, but not that from grapefruit leaves, inhibited cell viability of human pancreatic cancer cell line, MIA PaCa2. Finally, we identified two chlorophyll catabolites, pheophorbide-a and pyropheophorbide-a, in the larval frass extract. Pyropheophorbide-a reduces cell viability of and induces morphological changes in cells of MIA PaCa2; in addition, pheophorbide-a and pyropheophorbide-a inhibit the aggregation of amyloid β-protein (human, 1-42). Therefore, the chemical structure and biological activity of host plant components are affected by the P. memnon metabolic system. Our findings may contribute to the development of a bioprocess for the production of pheophorbide-a and pyrophephorbide-a from chlorophyll via the metabolic functions of P. memnon larvae.
he present review explores the causes, prevalence, diagnosis and sources of the triggering phototoxic plants. Phytophotodermatitis (PPD) is a cutaneous phototoxic inflammatory eruption resulting from contact with light-sensitizing botanical substances, known as furocoumarins, and long-wave ultraviolet A (UV-A, 320-380 nm) radiation. This Research has elevated our understanding of the phenomenon indicating the reaction or interaction between phototoxic plant containing photosensitizing compounds (eg furanocoumarins and psoralens) and ultraviolet radiation leading to hyperpigmentation of the exposed skin. Knowledge of the molecular pathway involved in the skin response to photosensitive compounds may give way for identifying potential therapeutic targets for management of the condition. The review 09.30.2024 JOURNAL OF P T
Furanocoumarins in citrus fruit can cause adverse drug interactions; however, there are few reports on furanocoumarins and drug interactions in common edible citrus cultivars except grapefruit. An ultra-performance liquid chromatography (UPLC)–based method for ten furanocoumarins in citrus fruit was established, and the effects on cytochrome P450 activity were investigated. Furanocoumarins were more abundant (2–43 times) in the peel than in the pulp. The pulp of Xiyou, Hongyou, and Navel orange exhibited P450 inhibition, with 50% maximal inhibitory concentration (IC50) values of 0.63, 0.67, and 1.02 mg/mL, respectively. The peel of all the varieties except Huyou and Satsuma exhibited P450 inhibition. Xiyou, Baiyou, Huangjinyou, Hongyou, Ponkan, and Navel orange had IC50 values of 0.33, 0.76, 0.38, 0.35, 0.43, and 0.37 mg/mL, respectively. These findings indicate that, except for Xiyou, Hongyou, and Navel orange, the consumption of the pulp of popular Chinese varieties of citrus fruit has a low risk of drug interactions, and the use of citrus products including peel may carry a significant risk of adverse drug interactions.
Organisms possess the capacity to biosynthesize a diverse array of natural compounds, particularly secondary metabolites, that have crucial therapeutic potential. However, it is important to acknowledge that some of these compounds demonstrate notable toxicity which is a complex issue influenced by various factors such as structural characteristics of the compound, dosage, individual variability, and exposure duration. The immediate adverse health effects of natural compounds involve acute poisoning, which might appear as a range of allergic reactions, as well as intense gastrointestinal distress. The possible long-term health consequences comprehend effects on the immunological, reproductive, and neurological systems and the possibility of cancer formation. Numerous studies have been conducted to substantiate the potential of secondary metabolites as viable candidates for medicinal applications. Nevertheless, a restricted body of research conducted by scholars has illustrated the toxicological effects of naturally occurring chemicals. The importance of ensuring the safe use of natural substances cannot be overstated, particularly given their increasing prominence as nutritional supplements, medicinal agents, and food products. Conducting a thorough study on the detrimental impacts of natural chemicals is significantly important. The primary focus of this chapter is an in-depth examination of natural compound diversity and their toxicity.
We report a Bismuth(III)triflate catalyzed novel, efficient and atom-economical one-pot three-component methodology for the synthesis of furo[3,2-c]-coumarins from arylglyoxals, 4-hydroxycoumarins and N-substituted anilines. While using N-methyl aniline, we have obtained...
Обзор посвящен фуранокумаринам – классу веществ, представляющих собой совмещение пиронового, бензольного и фуранового колец, обладающих системой сопряженных двойных связей (которая в ряде случаев может нарушаться). Эта группа соединений широко изучается в настоящее время благодаря своим фототоксическим и лекарственным свойствам. В работе рассмотрены фуранокумарины естественного происхождения, выявленные в семействе Umbelliferae (Зонтичные), или Apiaceae (Сельдерейные), структурировано их многообразие, описана история исследования, известные к настоящему времени этапы их биосинтеза, а также некоторые примеры их биологической активности в растении, в культуре клеток и при медицинском использовании.
Plant-derived coumarin (PDC) is a naturally occurring heterocyclic backbone that belongs to the benzopyrone family. PDC and its based products are characterized by low toxicity and high distribution in a variety of herbal treatments that have numerous therapeutic potentials. These include anticoagulants, antibacterials, anti-inflammatory agents, anticancer agents, antioxidants, and others. So, it may be appropriate to investigate the qualities and potential bioactivities of PDCs. This article provides an overview of the biomedical potentials, availability, and clinical use possibilities of PDCs, with a focus on their important modes of action, using information on various pharmacological qualities discovered. The data used in this study came from published research between 2015 and 2023. We reviewed a selection of databases, including PubMed, Scopus, Web of Science, and Google Scholar, during that period. In conclusion, because of their abundance in medicinal plants, the clinical biochemistry attributes of PDCs are currently of interest. In a variety of medical specialties, PDCs serve a useful role as therapeutic agents.
One‐pot procedure has been developed for the synthesis of novel β‐carboline tethered trans 2,3‐furocoumarins via assembling 1‐formyl‐β‐carbolines, 4‐hydroxycoumarins, and phenacyl bromides in pyridine under transition metal‐free conditions. The strategy was also found applicable to gram scale synthesis and a library of 40 molecules has been developed. The significant features of this operationally facile approach includes high efficiency, short reaction time, excellent yields, multicomponent character of the reaction, metal‐free mild reaction conditions, and a column chromatography free purification procedure.
We developed a facile approach for the preparation of a rare 2 H ‐furo[3,2‐ b ]pyran‐2‐one system. The suggested method is based on a two‐step process using unsubstituted allomaltol as a starting compound. The key stage of the considered route is a condensation of 2‐(2‐aryl‐2‐oxoethyl)‐3‐hydroxy‐6‐methyl‐4 H ‐pyran‐4‐ones with 1,1‐carbonyldiimidazole. The advantages of the presented method are commercially available starting materials and convenient experimental procedures including simple isolation of the target compounds. The structure of one of the 2 H ‐furo[3,2‐ b ]pyran‐2‐ones was confirmed by x‐ray diffraction.
The occurrence of coumarin-based photoactive compounds in essential oil has been a concern due to the adverse health effects it has on human health. A fit-for-purpose analytical method for major coumarin-based phototoxins is critical to guarantee the essential oils product safety and compliance with the regulatory requirements. Herein, a liquid chromatography-mass spectrometry (LC-MS) analytical method was developed to identify and quantify 25 coumarin derivatives in essential oils. The sample preparation procedure was optimized for essential oils to use selective solvent extraction to remove the limonene matrix interference. To achieve the optimal sensitivity and specificity, UHPLC column of biphenyl stationary phase was used for this analysis. An inter-laboratory validation study was conducted to evaluate the method performance. The limit of quantification (LOQ) for all target analytes were validated at 5 µg/g. Satisfactory recoveries were obtained for the majority of analytes in the range of 80-115%. Both the repeatability RSDr (within-laboratory) and reproducibility RSDR (between-laboratory) <10%. This method was demonstrated as applicable for the quality control testing of coumarin-based phototoxins in essential oils.
Background:
Thrombocytopenia is a common hematological disease caused by many factors. It usually complicates critical diseases and increases morbidity and mortality. The treatment of thrombocytopenia remains a great challenge in clinical practice, however, its treatment options are limited. In this study, the active monomer xanthotoxin (XAT) was screened out to explore its medicinal value and provide novel therapeutic strategies for the clinical treatment of thrombocytopenia.
Methods:
The effects of XAT on megakaryocyte differentiation and maturation were detected by flow cytometry, Giemsa and phalloidin staining. RNA-seq identified differentially expressed genes and enriched pathways. The signaling pathway and transcription factors were verified through WB and immunofluorescence staining. Tg (cd41: eGFP) transgenic zebrafish and mice with thrombocytopenia were used to evaluate the biological activity of XAT on platelet formation and the related hematopoietic organ index in vivo.
Results:
XAT promoted the differentiation and maturation of Meg-01 cells in vitro. Meanwhile, XAT could stimulate platelet formation in transgenic zebrafish and recover platelet production and function in irradiation-induced thrombocytopenia mice. Further RNA-seq prediction and WB verification revealed that XAT activates the IL-1R1 target and MEK/ERK signaling pathway, and upregulates the expression of transcription factors related to the hematopoietic lineage to promote megakaryocyte differentiation and platelet formation.
Conclusion:
XAT accelerates megakaryocyte differentiation and maturation to promote platelet production and recovery through triggering IL-1R1 and activating the MEK/ERK signaling pathway, providing a new pharmacotherapy strategy for thrombocytopenia.
A chemical investigation of Angelica acutiloba isolated 26 compounds: 11 coumarins (1–11), 11 phthalides (12–22), one sterol (23), two polyacetylenes (24, 25) and one bisbenzopyran (26). Of these, several were isolated from some sources for the first time: compound 26 from the family Umbelliferae, compound 23 from the genus Angelica L. and ten compounds (1, 3, 5, 7, 9, 13, 17–19 and 22) from A. acutiloba. The chemotaxonomic significance of these constituents is also discussed.
Glycoalkaloids are abundantly found among the members of the Solanaceae family. Potatoes (Solanum tuberosum L.), tomatoes (Solanum lycopersicum L.), and eggplant (Solanum melongena L.) are the most common sources of glycoalkaloids. The most predominant glycoalkaloids present in potatoes are α-solanine and α-chaconine, and several other glycoalkaloids such as β-chaconine, γ-chaconine, β1-solanine, β2-solanine, and γ-solanine are also present in small quantities. Tomatoes contain α-tomatine and dehydrotomatine, and eggplant contains solasonine and solamargine as their main glycoalkaloids. Glycoalkaloids, especially from potatoes e.g., α-solanine and α-chaconine, are known to cause gastrointestinal problems such as gastritis, gastrointestinal disturbance, nausea, vomiting, diarrhea, fever, low blood pressure, and, in high doses, cause a fast pulse rate along with neurological and occasional death in humans and farm animals. In recent years, an increasing number of toxicological events were reported by food contaminations with glycoalkaloids. Hence, it becomes very important to identify, analyze, and characterize different types of glycoalkaloids present in food items. This book chapter comprehensively covers sources, chemistry, pharmacological, and toxicological actions of glycoalkaloids present in food items.
Nuclear magnetic resonance (NMR) spectroscopy is a robust method, which can rapidly analyze compounds or their mixtures in complex matrices without separating or purifying them. This makes the technique ideal for analysis of foods and related products. NMR continues to be an underutilized methodology in the area of food authentication and analysis, mainly due to the high cost, relatively low sensitivity, and the lack of NMR expertise among food analysts. The aim of this chapter is to explore the role of NMR methodologies in the field of food science with a special focus on analysis of food toxins. An introduction of the basic principles of NMR related to the study of foods and nutrients is given. This is followed by a detailed description of metabolomics studies. NMR with metabolomics studies together make a powerful methodology to address the challenges faced in food science. Furthermore, a comprehensive overview of their recent applications in the areas of compositional analysis, food authentication, quality control, and human nutrition is provided. In addition, use of NMR techniques in the analysis of potential food toxins is discussed. Finally, future perspective of the use NMR-based studies in the identification and characterization of food constituents and toxins is presented.
Food toxins of natural origin cover a wide diversity of macromolecules; generated by plants, algae, fungi, or degraded products of metabolism with destructive effects even at very low concentration/dose or when consumed in sufficient quantities. These toxins have diverse chemical structures and may serve definite purposes in plants or are developed as biochemical protectant against predators, insects, or microbes. Glycoalkaloids, cyanide-generating compounds, enzyme inhibitors and lectins, and mycotoxins are some important examples of natural food toxins. The toxicity of food toxins relies on the level of toxins available as well as susceptibility of a given population. These toxins may lead to acute and chronic health issues whose clinical indications may range from minor gastrointestinal distress, neurological indications, and respiratory paralysis to fatality. Analysis of food toxins requires authentication of analytical techniques for screening, quantification, and identification of contaminants. Undeniably, chromatographic analytical approaches can analyze numerous natural food toxins in a given period of time, in a sensitive and selective manner, yielding toxins concentration accurately. Even though extensively used, these approaches are costly, consume a lot of time, and deliver data following a noteworthy time lapse. Furthermore, samples (food toxins) are damaged by analytical procedures. Thus, alternative approaches/substitutes such as IR spectroscopy are actually progressively advanced to deliver simple and rapid procedures for the detection of food toxins. IR spectroscopy is a non-destructive procedure; employed to authenticate and characterize samples in high throughput. The usefulness of IR spectroscopy has directed its usage in numerous applications which comprises chemistry of soil, cereals, agricultural produce, medicine, and so forth. Since it reviews the interactions between radiation and matter, IR spectroscopy is a suitable tool for carrying out analysis of food toxins in finished foodstuffs. This chapter delivers the advancement and potential prospective of IR spectroscopy as an alternate/substitute to prevailing techniques for the assessment of food toxins.
Alkaloids are the most important class of secondary plant metabolites that have been considered as the major source of phytomedicine. These alkaloids are a group of phytochemicals that contains two fused, five-membered rings that share a bridgehead nitrogen atom, forming a tertiary alkaloid. Pyrrolizidine alkaloids are known for their hepatotoxic activities, but are also reported to cause cancer. They are abundantly found in plant families such as Apocynaceae, Asteraceae, Boraginaceae, Compositae, Fabaceae, Leguminosae, Ranunculaceae, and Scrophulariaceae. Several medicinal plants contain pyrrolizidine alkaloids such as comfrey (Symphytum officinale), coltsfoot (Tussilago farfara), and petasites (Petasites japonicus), etc. Pyrrolizidine alkaloids are also present in milk (cows and goats), honey, staple foods, herbal teas, and herbal medicines. In recent years, an increasing number of toxicological reports revealed food contaminations with pyrrolizidine alkaloids. Hence, it becomes very important to identify, analyze, and characterize different types of pyrrolizidine alkaloids present in food items. In this book chapter, sources, chemistry, pharmacological, and toxicological actions of pyrrolizidine alkaloids will be discussed.
Castor (Ricinus communis; family: Euphorbiaceae) oil extracted from castor seed is a nonedible, nontoxic, yellowish color liquid that has become an essential bioresource material for industrial uses. The castor oil is rich in ricinoleic acid; this is a key precursor of the production of lactones. The presence of a double bond and hydroxyl and carboxylic groups with a long hydrocarbon chain in ricinoleic acid proposes several possibilities for converting it into valuable compounds. γ-Decalactone is an aroma compound having peach-like essence, generally utilized in food industries. Lipase-mediated biotransformation is used to produce γ-decalactone from ricinoleic acid under controlled conditions. Several studies and industrial approaches have explained the genetic and metabolic engineering and bioprocess engineering strategies in the enrichment of aroma compounds, but few studies have been available on the utilization of castor oil as a natural raw material for the synthesis of aroma compounds. As a result, this review draws attention to the importance of castor oil in the production of value-added aroma compounds with their estimated global market prospective. The review gives information about the properties of castor oil and its geographical accessibility and its exploitation as a bio-based resource for the production of various value-added materials. In addition, this review emphasizes the utilization of ricinoleic acid or castor oil as a renewable source for the production of aroma compounds. Though chemical transformation for the production of lactone derivatives is known, the products are chiral mixtures. On the other hand, the lipase-based conversion is enantiospecific, and this product is categorized as nature-identical and considered safe for using in food products.KeywordsCastor oilFlavourFragranceLipase medicated biotransformation
Xanthotoxin (XAT) is a natural furanocoumarins, a bioactive psoralen isolated from the fruit of the Rutaceae plant Pepper, which has received increasing attention in recent years due to its wide source and low cost. By collecting and compiling literature on XAT, the results show that XAT exhibits significant activity in the treatment of various diseases, including neuroprotection, skin repair, osteoprotection, organ protection, anticancer, antiinflammatory, antioxidative stress and antibacterial. In this paper, we review the pharmacological activity and potential molecular mechanisms of XAT for the treatment of related diseases. The data suggest that XAT can mechanistically induce ROS production and promote apoptosis through mitochondrial or endoplasmic reticulum pathways, regulate NF‐κB, MAPK, JAK/STAT, Nrf2/HO‐1, MAPK, AKT/mTOR, and ERK1/2 signaling pathways to exert pharmacological effects. In addition, the pharmacokinetics properties and toxicity of XAT are discussed in this paper, further elucidating the relationship between structure and efficacy. It is worth noting that data from clinical studies of XAT are still scarce, limiting the use of XAT in the clinic, and in the future, more in‐depth studies are needed to determine the clinical efficacy of XAT.
Novel 4-oxo-4H-furo[3,2-c]pyran-3-carboxylates and 4-oxo-4H-furo[3,2-c]chromene-3-carboxylates were prepared from available alkyl 3-bromo-3-nitroacrylates and 4-hydroxy-6-
methyl-2H-pyran-2-one or 4-hydroxycoumarin, respectively. Their structures were confirmed by NMR and X-ray data.
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.
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.
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.
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
A linear furocoumarin phytoalexin response was observed in stressed celery (Apium graveolens). Heretofore, linear furocoumarins found in diseased c
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.
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.
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 results also suggested, first, an interaction between UV (280–400 nm) induced photoproducts and psoralen photoadducts and secondly, a strain difference in the oncogenic effects of this interaction.
The ability of furocoumarins to participate in the PUVA (Psoralen+UV-A) therapy against skin disorders and some types of cancer, is analyzed on quantum chemical grounds. The efficiency of the process relies on its capability to populate its lowest triplet excited state, and then either form adducts with thymine which interfere DNA replication or transfer its energy, generating singlet molecular oxygen damaging the cell membrane in photoactivated tissues. By determining the spin–orbit couplings, shown to be the key property, in the intersystem crossing yielding the triplet state of the furocoumarin, the electronic couplings in the triplet–triplet energy transfer process producing the singlet oxygen, and the reaction rates and lifetimes, the efficiency in the phototherapeutic action of the furocoumarin family is predicted as: khellin
The objective of the present study was to develop a practical strategy for the identification of metabolites following the in vivo metabolism and in vitro microbial biotransformation of isoimperatorin using liquid chromatography hybrid triple quadrupole-linear ion trap mass spectrometry (LC/QTRAP-MS) and liquid chromatography time of flight mass spectrometry (LC/TOF-MS). As a result, 19 metabolites were characterised in rat urine, plasma, bile and faeces after the oral administration of isoimperatorin and 13 products were identified in the sample from the transformation. Four metabolites were prepared by in vitro microbial biotransformation, and one was confirmed to be a novel compound. The side chain of isoimperatorin was found to be the primary metabolic site that underwent oxidation metabolism both in vivo and in vitro, and the metabolism of isoimperatorin in vivo and in vitro has good correlation. This is the first study of the metabolism of isoimperatorin in vivo.
In one form or another psoralens have been in use dating back to biblical times for the treatment of depigmented patches of skin. However, it has only been in the past 40 years that the structure and function of psoralens have been elucidated. Although several volumes have been published on photobiology and photomedicine, no one volume has ever been devoted to the psoralen photobiology. In these two volumes we focus on the properties and uses of photoactivated psoralens.In these volumes the various aspects of psoralens are presented in a review of the field as it stands in mid 1986. In retrospect, we may find that this particular time was crucial in the development of new therapeutic modalities as many of the applications of modem molecular biology are beginning to impact on the practice of medicine.This book was written with two purposes in mind. First, to serve as an update (the last collective review of the field was in 1982). Second, it is hoped that newcomers to the fields of photobiology andphotomedicine both scientists and clinicians would find it a useful introduction.
A method is described to determine the 8-methoxy-psoralen (8-MOP) concentration in vivo in the skin by means of high-performance liquid chromatography (HPLC). Skin and blood samples were taken from 80 rats at specific intervals after oral administration of [³H]8-MOP. The pharmacokinetic results obtained for the skin levels were compared to the blood levels. In addition, liquid scintillation counting (LSC) was done on all the samples to compare the concentrations of 8-MOP plus metabolites to the concentrations of 8-MOP alone.
There was a good correlation between the 8-MOP skin and blood levels. The values obtained with LSC were higher in function of time than the corresponding values obtained by HPLC, which indicates the presence of metabolites in both the skin and the blood. No statistically significant difference in the time of peaking was noted for the skin and blood levels. The blood levels seem to be a good parameter for the 8-MOP skin concentration.
Grapefruit (Citrus paradisi Macf.) sales and crop value have declined during the last decade. One reason is consumer concerns about possible drug interactions. Coadministered grapefruit increases the bioavailability of some medicines because it contains furanocoumarins that inhibit an intestinal enzyme (cytochrome P450-3A4 or CYP3A4) that normally metabolizes these drugs. Only drugs metabolized by intestinal CYP3A4 are significantly affected when taken with grapefruit juice, but the magnitude of the effect varies considerably between studies, indicating that there are differences in the amount of components responsible for CYP3A4 inhibition in commercial grapefruit juices. Content variation of 6,7-dihydroxybergamottin, bergamottin, and 6 furanocoumarin dimers were determined for 58 commercial grapefruit juices collected over 2 seasons. The content of 6,7-dihydroxybergamottin ranged from 0.2 to 7.7 ppm in all juices tested, and averaged 1.8 ± 0.85 ppm in the red compared with 2.9 ± 2.07 ppm for white grapefruit juices. Bergamottin content ranged from 1.6 to 7.3 ppm for all juices and averaged 3.4 ± 0.98 and 4.2 ± 1.23 ppm and in red and white grapefruit juices, respectively. Only 1 dimer varied significantly between the red and white juice types. Dihydroxybergamottin and 2 dimer compounds were significantly lower in shelf-stable or nonrefrigerated products compared with refrigerated products whereas bergamottin and 1 dimer compound occurred at higher levels in the shelf-stable products. Individual measured dimer compounds varied up to 60-fold in all juices, but the sum of all 6 dimers varied only 14-fold. The clinical significance in terms of CYP3A4 inhibition is uncertain. The presence of 3 new furanocoumarin dimers are also reported.
Normal levels of total furocoumarins in fresh parsnip roots are as high as 96 ppm (wet weight). In older spoiled and diseased parsnips freely available in grocery stores these values may be increased by 2500%. So high are the amounts in some instances, that mixed crystals of furocoumarins can be detected on the surfaces of the parsnip roots by both conventional low powered microscopy and SEM. The principal crystal form was angelicin but the presence of psoralen, 5-MOP and 8-MOP was confirmed by HPLC, TLC, photobiological assay and analysis of mass spectra.
A combination of ultrasensitive bioassay and HPLC analysis was employed to analyse the garden carrot for furocoumarins. The earlier reported negative findings were due to the relatively insensitive methods of detection. Low levels of two furocoumarins, 8-MOP and 5-MOP were detected in all parts of fresh carrot plants for the first time. Occasionally one or two other unknown photoactive compounds were also present. Diseased carrot displayed increased levels of 8-MOP and 5-MOP; psoralen was also detected. In this respect carrot is capable of a phytoalexin response similar to celery.
Several approaches are described aiming at a better understanding of the genotoxicity of psoralen photoinduced lesions in DNA. Psoralens can photoinduce different types of photolesions including 3,4- and 4′,5′-monoadducts and interstrand cross-links, oxidative damage (in the case of 3-carbethoxypsoralen (3-CPs)) and even pyrimidine dimers (in the case of 7-methylpyrido(3,4-c)psoralen (MePyPs)). The characterization and detection of different types of lesions has been essential for the analysis of their possible contributions to genotoxicity. For example, oxidative damage photoinduced by 3-CPs can be detected by the formamidopyrimidine glycosylase (FPG) protein. Furthermore, it is shown how the presence of MePyPs induced monoadducts may interfere with the photoreactivation of concomitantly induced pyrimidine dimers, how the ratio of monoadducts and interstrand cross-links (CL) affects the occurrence of double-strand breaks during the repair of photolesions and genotoxicity. In vitro treatment of yeast plasmids, followed by transformation, also indicates that the repair of photoadducts on exogenous DNA differs for 8-methoxypsoralen (8-MOP) induced mono- and diadducts and for monoadducts alone. The recombinational rad52 dependent pathway is not needed for the repair of 8-MOP induced monoadducts. The results obtained suggest that the genotoxic effects of psoralens are conditioned by the nature, number, ratio and sequence distribution of the photolesions induced in DNA.
Since the early 1990's, grapefruit juice has been implicated in drug interaction with various furanocoumarins (FCs) now associated with the effect. Although FCs are present in various fruits and vegetables, it is their presence in grapefruit that has attracted the most attention. Studies have shown that FCs in grapefruit juice can vary significantly and from multiple causes. Most of all, FCs are stress-induced molecules, their levels affected by many factors ranging from UV exposure to insect infestation. There are also varietal and seasonal factors. In this study, juice processing and storage parameters were investigated. Prolonged fruit storage prior to processing and most steps involved in juice processing had little influence on the levels of 6′,7′-dihydroxybergamottin (DHB), paradisin C, or bergamottin. However, products that were hot filled or stored at room temperature had lower amounts of DHB and paradisin C and higher amounts of bergaptol compared to juices that were not hot filled and stored at refrigerated temperatures. Both DHB and paradisin C are potent CYP3A4 inhibitors, while bergaptol is a very weak inhibitor. Bergamottin amounts decreased to a lesser extent. Therefore, grapefruit juice products that were hot filled or have been stored at room temperature for an extended period of time will have a reduced drug interaction potential.
Practical Application: This research provides information on how grapefruit drug interaction potential of grapefruit juice products are affected by processing and storage of juice products. Shelf stable products stored at room temperature in cans and glass containers will have lower levels of FCs compared to fresh products made from the same juice. Those wishing to minimize drug interaction potential in grapefruit products may do so by heating to pasteurization temperatures for 30 to 60 min. However, this will only lower and not eliminate the drug interaction potential.
By 1977, psoralen and ultraviolet A (PUVA) was established as a highly effective therapy for psoriasis. Because of concerns about potential long-term adverse effects, particularly cancer, the PUVA Follow-Up Study was established to assess long-term risk and benefits of PUVA.
We sought to determine the association of certain squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) risk with exposure to PUVA.
For nearly 30 years, this prospective cohort study of 1380 patients with psoriasis first treated with PUVA in 1975 to 1976 documented exposures and incident events including biopsy-proven skin cancers.
From 1975 to 2005, 351 of 1380 (25%) cohort patients developed 2973 biopsy-proven SCC and 330 (24%) developed 1729 BCCs. After adjusting for age, gender, and significant confounders, the risk of developing one or more SCC in a year was strongly associated with total number of PUVA treatments (350-450 vs <50 treatments, incidence rate ratio [IRR] = 6.01, 95% confidence interval [CI] = 4.41-8.20). When all tumors are included this risk is significantly higher (IRR = 20.92, 95% CI = 14.08-31.08). Corresponding risks for BCC were much lower (person counts IRR = 3.09, 95% CI = 2.36-4.06; tumor counts IRR = 2.12, 95% CI = 1.47-3.05).
This was an observational prospective study of a cohort with severe psoriasis. An unknown factor associated with higher dose exposure to PUVA in our cohort that was not included in our analysis could account for the observed associations.
Exposure to more than 350 PUVA treatments greatly increases the risk of SCC. Exposure to fewer than 150 PUVA treatments has, at most, modest effects on SCC risk. Even high-dose exposure to PUVA does not greatly increase BCC risk. The risks of SCC in long-term PUVA-treated patients should be considered in determining the risk of this therapy relative to other treatments for severe psoriasis.
Furocoumarins are phototoxic and photogenotoxic natural plant constituents occurring in cosmetics, food and drugs. Grapefruit juice is considered as a major dietary source of furocoumarins although few is known about the variability of furocoumarins in grapefruit juice. We analyzed the major furocoumarins in eight commercial grapefruit juices and in freshly prepared juices made from pink grapefruit obtained from German retailers. Bergaptol was the major furocoumarin in commercial juices, followed by bergamottin and 6',7'-dihydroxy-bergamottin (DHB), whereas an inverse picture (DHB>bergamottin>bergaptol) was obtained in freshly prepared juices. Results from different batches of a single brand of commercial juice, purchased over a period of 7 months, revealed a variability of about 50% for the individual furocoumarins and the sum. In a study with healthy volunteers, consumption of 900 ml commercial grapefruit juice (containing 12.5mg bergaptol, 6.9 mg bergamottin, and 0.6 mg DHB) resulted in an average urinary excretion of 0.36 mg free plus 13.23 mg conjugated bergaptol within 6h. Other furocoumarins were not found in urine. Thus, other grapefruit furocoumarins were obviously converted in the human body, at least in part, into bergaptol excreted in urine, since the excreted amount of bergaptol exceeded the consumed one.
Furocoumarins or psoralens represent a class of photosensitizers whose use level is likely to be restricted to 1 ppm in cosmetic products by the EU. A reversed-phase HPLC method was developed to separate the 15 main furocoumarins present in citrus oils. Quantification by UV, fluorescence, or mass detectors was compared in terms of linearity and limit of detection. Cold-pressed oils of different citrus species were analyzed using this method. This method could be implemented in quality control laboratories equipped with an HPLC system and a UV diode array detector. Because of possible coelutions, the UV-spectral data should be carefully examined to avoid misleading interpretations of peaks.
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The health maintaining properties of citrus consumption are attributed to the wide assortment of bioactive compounds. Consumption of grapefruit along with certain medications, however, is posing a risk of drug toxicity and side reactions. The first study involved isolation of bioactive furocoumarins with a combination of chromatographic techniques and synthesis. Five furocoumarins namely, dihydroxybergamottin, paradisin A, bergamottin, bergaptol and geranylcoumarin were isolated from grapefruit and series of furocoumarin monomers and paradisin A were synthesized. The second study involved influence of pre- and post-harvest factors on the levels of furocoumarins in grapefruit juice. Considerable differences were observed in the levels of these compounds in different grapefruit cultivars. Ray Red showed the lowest levels of all three furocoumarins and Duncan contains the highest amount of DHB and bergamottin, where as the highest levels of paradisin A was observed in Star Ruby. The highest levels of DHB and bergamottin were found in Flame cultivar grown in California. The changes in the levels of these furocoumarins during the season in Rio Red and Marsh White grapefruit cultivars were evaluated. The third study investigated biological activities of grapefruit juices and furocoumarins. Grapefruit and Pummelo juices were found to be potent inhibitors of cytochrome CYP3A4 and CYP2C9 isoenzymes at 5% concentration while CYP2D6 was less affected. Among the five furocoumarins tested, the inhibitory potency was in the order of paradisin A>dihydroxybergamottin>bergamottin>bergaptol>geranylcoumarin at 0.1 µM to 0.1 mM concentrations. A fourth study investigated the effect of furocoumarins on bacterial auto-inducer signaling, and found that furocoumarins are potent inhibitors of AI-1 and AI-2 activities at 0.01% concentration. In a fifth study, involving synthesized furocoumarin monomers and dimer on anti-proliferative activities on normal and cancer cell lines, furocoumarins found to be non-toxic to normal cells. However, bergamottin showed a significant anti-proliferative activity in HT-29 and MCF-7 cell lines. This dissertation indicates that furocoumarins are bioactive compounds from grapefruit juice with potent inhibitory property of major drug metabolizing cytochrome P450 isoenzymes. Furocoumarins show a considerable variation between varieties, location and season. These results corroborate the involvement of furocoumarins in grapefruit drug interaction.
Furocoumarins are phototoxic and photomutagenic natural plant constituents found in many medicinal plants and food items. Since plants contain mixtures of several furocoumarins, there is a need for a comparative risk assessment of a large number of furocoumarins. Previously, we have introduced the concept of relative Photomutagenicity Equivalency Factors (PMEFs) derived from the slope of the concentration-response curve of photomutagenicity of individual furocoumarins in V79 cells using the HPRT mutation assay in the presence of UVA irradiation at 125mJ/cm(2). Here we have applied this method to the furocoumarins bergamottin, isopimpinellin and psoralen using 5-methoxypsoralen (5-MOP) as a reference compound with a PMEF of 1.0. We found that neither bergamottin nor isopimpinellin, two furocoumarins abundant in plants, food etc., exerted any significant photomutagenicity while psoralen was clearly photomutagenic with a PMEF of 0.36. Similarly, isopimpinellin was not phototoxic in V79 cells, while bergamottin showed some cytotoxicity which, however, was completely independent of UVA irradiation. Only psoralen was photocytotoxic showing a similar concentration-response relationship for photomutagenicity, and for photocytotoxicity (at 72h after irradiation). Data from the micronucleus assay for DNA damage at 20h after irradiation were in complete agreement with the HPRT mutation data. Our findings indicate that individual furocoumarins differ enormously in their photomutagenic potency, and that a specific toxicological risk assessment is required for each furocoumarin instead of an assessment based on the sum of furocoumarins in a given sample.
Phototoxic and photo-genotoxic furocoumarins occur, e.g., in citrus species, parsnip, parsley, celery, and figs. They exhibit phototoxic and photo-genotoxic properties in combination with UV radiation, while less is known about the phototoxicity of the coumarin derivative limettin mainly found in limes and lemons. Risk assessment of dietary furocoumarins is based on a threshold approach and on estimates of 1.2-1.45 mg for the average daily exposure for adults via the diet in several countries. In these estimates, the major contribution to overall daily exposure has been attributed to citrus-flavored non-alcoholic beverages, in spite of a lack of analytical data for those products. Therefore, we analyzed a number of furocoumarins in a variety of citrus-containing beverages and included limettin in the pattern of analyzed constituents. Our findings provide strong evidence that grapefruit juice and not citrus-flavored non-alcoholic beverages is the major source of furocoumarin exposure in a Western diet. Based on these findings it can be assumed that the average dietary exposure to furocoumarins is about 3-fold lower than previously estimated, i.e. in the range of 548 and 2237 microg/day for the average and high consumer, respectively. The coumarin derivative limettin was mainly found in lime products.
The distribution of 3H-8-methoxypsoralen has been studied in rats by whole body autoradiography. The highest organ concentration were seen 1 hour after dosing. The most pronounced accumulation was found centriblobular in the liver, corticomedullary in the kidneys, and in the cortex of the adrenals. The concentrations in these organs were approximately six times higher than in the blood. Other organs showed concentrations similar to blood levels. Illumination with UVA (10 J/cm2) increased the concentrations in the subcutis.