Coumarin toxicity. MeSH terms Coumarins / toxicity* Humans .

Coumarin toxicity Recent research has highlighted its anti-inflammatory properties, positioning it as a promising candidate for treating inflammatory disorders such as rheumatoid arthritis, asthma, and Coumarin toxicity . Research has established a correlation between excessive mitochondrial ONOO − production and various diseases. Therefore, its concomitant use with hepatotoxic drugs should be avoided. / Coumarin, cinnamon, plant matrix, toxicology, risk assessment Einleitung Im Augustheft der Deutschen Lebensmittel-Rundschau findet sich unter dem Titel „Zimt und Cumarine: bittere ‚Wahrheiten‘ – Beitrag zur Extrapolation von Risiken“ ein Artikel (Schmidt und Müller, 2007), in dem die Autoren zur aktuellen Diskussion um Zimt und Cumarin Stellung neh-men und dabei Hier sollte eine Beschreibung angezeigt werden, diese Seite lässt dies jedoch nicht zu. For the carcinogenic effect, a genotoxic mechanism was considered possible, but was discounted by the European Food Safety Authority in 2004 based on new evidence. , 2002) and yields CE, a reactive intermediate. The action decreases when substituents are added to vinylbenzene at the para position. 228-239. Auraptene, a coumarin from Citrus species was tested for acute oral toxicity in rats in doses of 125–2000 mg/kg bw, not causing mortality or clinical signs of toxicity. A series of coumarin derivatives incorporating different functional groups were synthesized and tested for their antiproliferative activity against breast cancer and Keywords: Coumarin derivatives, Structure-Activity Relationship, Biological effects, Pharmacological properties, Toxicity, Synthesis, Drug candidates Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. has been used to treat “1 kg of [cassia cinnamon] powder contains approximately 2. compared the toxicity of 0. For the carcinogenic effect, a genotoxic mechanism was considered possible, but Auraptene, a coumarin from Citrus species was tested for acute oral toxicity in rats in doses of 125–2000 mg/kg bw, not causing mortality or clinical signs of toxicity. Risk assessment of coumarin in the Norwegian population. , 2003; Ratanasavanh et al. 1956 Nov;118(3):348-58. g. Price et al. vulnerable patients, but also to fully exploit coumarin as a pharmaceutical for patients . The present study is designed to investigate the acute toxicity of newly discovered heterocyclic frameworks derived from the coumarin backbone, namely coumacine I and coumacine II. The use of zebrafish vertebrate models in preclinical drug discovery is now a widely accepted tool to conduct rapid in vivo tests. Toxicology and Applied Pharmacology 1989 , 97 (2) , 311-323. Other sources of information Coumarin is a natural chemical compound in many plants. In a subacute test, auraptene was administered to rats In dose and toxicity studies conducted by Marshall et al. 1 mm hydrocortisone 21hemisuccinate. This review Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. The Carcinogen Identification Committee (CIC) advises and assists OEHHA in compiling the list of chemicals that cause cancer as required by Health However, this coumarin also induced gastrointestinal toxicity and produced a reduction on nutrient absorption, which caused a reduction in the weight of animals and an increase on feed intake . The patient had been taking statin for J Biol Response Mod 8:116–121PubMed Gallicchio VS, Hulette BC, Harmon C, Marshall ME (1989) Toxicity of coumarin (1,2-benzopyrone) on human peripheral blood mononuclear cells and human and murine bone marrow progenitor stem cells. persicae aphids was promising, in agreement with the criteria recently outlined by Ikbal and Pavela (2019), where it is generally possible to consider as promising substances those exhibiting LC 90 less than 2g L 1 (0. Among the diverse possible strategies to reach this aim Toxicology and risk assessment of coumarin: Focus on human data. These tumors are not fatal and do not metastasize. Mayer S (1990) Poisons - Coumarin derivatives. Umbelliferone, a common coumarin compound found in almost all higher plants, has been extensively studied for its pharmacological effects in different disease models and doses with complex action mechanisms. May cause mouth sores. 16-DAY Similarly, it has been determined that toxicity from in vitro coumarin varies by species. 5 X 106 were COUMARIN TOXICITY IN RAT HEPATOCYTES 313 seeded in 50-mm dishes with 3 ml RPMI 1640 culture medium containing 5% fetal calf serum, 50 gg/ml gentamicin, I jum insulin, and 0. Es besitzt einen angenehmen, vanille- bzw. Despite the compound’s toxicity, the plants that contain coumarin have many health benefits. Isolated coumarin must not be added to foods Six coumarins (dicoumarol, coumarin, osthole, esculetin, psoralen, bergapten, Figures 2A–F) had varying levels and types of toxicity ranging from excessive bleeding due to inhibition of blood clotting (anticoagulants), cytotoxic effects causing hyperventilation, tremor, & photophobia, pulmonary haemorrhage, carcinogenic activity, severe neurotoxicity, Coumarin is an organic compound that can be obtained from a variety of plants, natural spices, and foods, such as cassia, cinnamon, sweet clover, green tea, peppermint, celery, bilberry, lavender, honey, and carrots, The detoxification of coumarin in humans is mainly mediated by CYP2A6 32, 35, 45), which may imply variations in the susceptibility to coumarin toxicity as a result of genetic polymorphisms in the metabolizing enzyme 46, 47, 48). heuartigen Geruch. Skin sensitization, Category 1. To do so, a Toxicity. Natural Coumarin Shows Toxicity to Spodoptera litura by Inhibiting Detoxification Enzymes and Glycometabolism August 2023 International Journal of Molecular Sciences 24(17):13177 The SCF delivered an opinion on coumarin in 1994 ( Scientific Committee for Food, 1997 ). The average intakes of food-derived coumarin are estimated to be 1−3 mg/day, while a ten-times higher level is expected in Coumarin, a plant secondary metabolite, has various pharmacological activities, including antioxidant stress and anti-inflammatory effects. Coumarins are benzopyrones, of which the Coumarin is commercially available with a minimum purity of 99% (Rhodia, undated). Betsy D. Rat liver toxicity and liver tumors have been recorded at doses greater than or equal to 150 mg/kg body weight in rats. However, research suggests that eating too much coumarin may cause liver toxicity and damage. 004% in ceylon). Vet Rad 34 (6), 391-396 VetMedResource. In this study, we found that natural coumarin significantly inhibited the growth and development of Spodoptera litura larvae through toxicological assay. It has been reported in many varieties of African plant families including Adoxaceae, Asclepidiaceae, Aspiaceae, Capparidaceae, Compositae, Ebenaceae, Fabaceae, Lauraceae, Meliaceae, Moraceae, Papilionaceae, Ptaeroxylaceae, Rutaceae, etc. This is above the Tolerable Daily Intake (TDI) for coumarinrecommended by the European Food Safety Authority (EFSA). , 2002). 6,7 Coumarin is widely used as a fragrance in cosmetics, perfumes and soaps. Although considered a non-genotoxic agent, coumarin has been shown to produce tumours in rodent species (reviewed in Privileged structures have been widely used as an effective template for the research and discovery of high value chemicals. 1), was selected to examine the influence of different characteristic groups on skin permeability. Authors L W HAZLETON, H K MURER, R THIESSEN Jr, T W TUSING, B R ZEITLIN. Return to reference 4 referrer. In Chinese hamster ovary cells, coumarin induced sister chromatid exchanges in the absence of S9, and chromosomal Coumarin and indandione toxicity may also increase the fragility of blood vessels, exacerbating the problem by causing bleeding at sites that are not subject to trauma 6. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins There are two general classes of anticoagulant rodenticides: the coumarin compounds (warfarin, coumafuryl, brodifacoum, and bromadiolone) and the indanedione compounds (diphacinone, pindone, valone, and chlorophacinone). The toxicity of coumarin has raised some concerns and food safety authorities have set a maximum limit of 2 mg/kg for foods and beverages in general, and a maximum level of 10 mg/l for alcoholic beverages. It is found in tonka beans and extract of tonka beans, among other natural sources, and is also synthesized. Although the short half-life of CE precludes the direct examination of its effects (Born et al. Rodents metabolize it mostly to 3,4-coumarin epoxide, a toxic, unstable compound that on further differential metabolism may cause liver cancer in rats and lung tumors in mice. Given its relatively low persistence, coumarin is expected to readily degrade in the environment. Hence the relevance of coumarin to the toxicity of STPs and its inclusion in the FDA’s list of harmful and potentially harmful compounds list is questionable. Lake, B. 935 g/cm 3 at 20 °C (Lide, 1999) Spectroscopy: Infrared (prism [1691]; grating [270]), ultraviolet [492], nuclear magnetic resonance (proton, [10407, V-225]; C-13 [242]) and mass spectral data have been reported (Sadtler This article reviews the literature on coumarin, a natural product used to treat lymphoedema, and its potential liver toxicity. Coumarin is a natural product which exhibits marked species differences in both metabolism and toxicity. , 2010). cinnamon (which contains coumarin) on the uptake and metabolism of coumarin as well as human toxicity data from the use of coumarin as a drug have now become available. Molecular Nutrition & Food Research, 54(2), pp. The toxicity of coumarin has raised some concerns and food safety authorities have set a maximum limit of 2 mg/kg for foods and beverages in general, and a maximum level of 10 mg/l for alcoholic beverages. The Both systemic toxicity case studies (phenoxyethanol and coumarin) were explored and challenged by workshop attendees, with an emphasis on the ability of the case study to support robust safety decision-making. " These foods usually contain such a low Among the coumarin analogs, esculetin, which possesses orthodihydroxy coumarins, showed the strongest protective effect against CCl(4)-induced liver damage, followed by scoparone, 4-methylumbelliferone and coumarin, respectively. In this review, an overview of the pharmacology, pharmacokinetics, and toxicity of scopoletin is provided. Keywords: National Institutes of Health; National Center fo Coumarin is moderately toxic to the liver and kidneys of rodents, with a median lethal dose (LD50) of 293 mg/kg in the rat, a low toxicity compared to related compounds. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects Re-assessment of coumarin toxicity and established a new TDI of 0. Concerns about coumarin's safety have also been raised by toxicity testing conducted by the Natio Coumarin compounds with high pharmacological activity, high bioavailability, low toxicity, and minor side effect are being studied by various research groups worldwide. When consuming foods and products Human hepatocytes were sensitive to coumarin toxicity only at a concentration of 1 mmol/L. , mild dizziness, diarrhoea, vomiting) after coumarin exposure is rare and generally associated with high doses administered in clinical therapies, recent studies report a connection of coumarin with liver tumours in rats and mice and with Clara cell toxicity and lung tumours in mice . that are Cassia (or regular) cinnamon is a rich source of coumarin. It is known that coumarin can cause liver toxicity in several species, and it is considered a non-genotoxic carcinogen in rodents. Thus, evaluation of coumarin cytotoxicity in humans coumarin toxicity. 51 Furthermore, coumarin derivatives like N′-{2-(2-[3,4-dichlorobenzyl]-4-oxoquinazolin-3[4H]-yl)acetyl}-2-oxo-2H-chromene-3-carbohydrazide and N′-{2-(2-[4-bromobenzyl]-4-oxoquinazolin-3[4H]-yl)acetyl}-2-oxo-2H Coumarin Metabolism, Toxicity and Carcinogenicity: Relevance for Human Risk Assessment B. These five compounds were chosen due to their specific structure characters, which was beneficial to discuss the impact of specific moieties on To investigate further the mechanism of coumarin toxicity, we studied the effects of various methyl derivatives, in particular 3- and 4-methylcoumarins and 3,4-dimethylcoumarin, which might be expected to affect the formation of a putative 3,4-epoxide intermediate, on the survival of rat hepatocytes in primary culture (Fentem et al. The critical effect identified for characterizing the risk to human health for coumarin 1 was developmental toxicity. It has been postulated that in the absence of detoxification through 7-HC, epoxidation is favored in rats leading to Background. , 2015; Mousavi et al. Toxicity trend from most to least toxic coumarins for group 2 is given below Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Johnson-Arbor says both types of cinnamon contain coumarin, "a group of compounds that are found in different types of foods and plants and vegetables that we eat every day. Carlton, in Encyclopedia of Toxicology (Second Edition), 2005 Uses. 1. Other species, including the Syrian hamster, are seemingly resistant to coumarin-induced toxicity. Machine learning approaches identified coumarin dose and cancer type as the most influential determinants of toxicity, while treatment duration and the specific coumarin displayed weaker effects Moreover, recent studies regarding oral toxicity of coumarin derived products have already been published using UMB (7-hydroxycoumarin associated to β-D galactopyranoside), isolated from the stem of Aegle marmelos (Rutaceae), found everywhere in India [3, 42], also revealed that the synthetic derived 4-methylesculetin has a non-toxic nature, having no signs Coumarin is a natural product well known for its pleasant vanilla-like odor. Conclusions Coumarin is not effective therapy for women who have lymphedema Peroxynitrite (ONOO −) is a transient and reactive oxidant with significant roles in numerous biological processes. Food and Chemical Toxicology, 37(4), pp. Survey on coumarin concentrations in Norwegian foods and conduction of intake calculations for children and adults. 2 Repeat-dose toxicity_____ 13 4. , 1997), the role of CE as a liver and lung toxicant is supported by studies coumarin-related toxicity 10. Chronic oral Cumarin oder Kumarin ist ein natürlich vorkommender, aromatischer sekundärer Pflanzenstoff aus der Gruppe der Phenylpropanoide. Samples from conditions G, T, and M at 6 h were collected for total There were limited health effects (hazard) data for coumarin 1; therefore, a comparative (read-across) approach using data from a similar chemical was used for assessing potential health effects. Recent studies show that certain levels of coumarin may have additional pharmaceutical purposes, but high dosages can cause various issues. 1 mg of coumarin. These Acute toxicity, Oral (Category 3), H301 Acute aquatic toxicity (Category 3), H402 Chronic aquatic toxicity (Category 3), H412: GHS Label elements, including precautionary statements Pictogram Signal word : Danger: Hazard statement(s) H301 - Toxic if swallowed H402 - Harmful to aquatic life H412 - Harmful to aquatic life with long lasting effects: Precautionary statement(s) P264 - In conclusion, both sodium bentonite and coumarin supplementation was beneficial in ameliorating the toxicity of aflatoxin B1. Studies of the Norwegian (Fotland et al. There is a clear threshold for effect, with the carcinogenic response in rodents being secondary to the target organ toxicity. Cumarin ist die Stammverbindung der Stoffgruppe der Cumarine, die als Derivate des Cumarins dessen Coumarin is a component of natural flavourings including cassia, which is widely used in foods and pastries. There are marked coumarin-inducedhepatotoxicity. The food and Drug Administration banned coumarin use in food because of reports that coumarin produced hepatotoxicity in rodents. Finally, safety and Hepatotoxicity associated with food-derived coumarin occurs occasionally in humans. Coumarin represents a privileged scaffold for medicinal chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic transformation into a large variety of functionalized coumarins. By transcriptomic sequencing, 80 and 45 differentially expressed genes (DEGs) related to Berry C R et al (1993) Thoracic radiographic features of anticoagulant rodenticide toxicity in 14 dogs. In the last years, these natural compounds have been gaining an increasing attention In this regard, it has been reported that various coumarin derivatives selectively inhibit the enzyme MAO-B, implicated in Alzheimer’s disease, and prevent Aβ1-42 aggregation, with low toxicity in the studied cells lines. Moreover, hepatotoxicity did manifest itself as severe single cell necrosis and minimal centrilobular necrosis, as observed by histopathological observations in livers of rats treated with 200 mg/kg coumarin. protocols have prohibited the utilization Coumarin, one of the main components of cinnamon, has been indicated to have hepatotoxic, and carcinogenic effects (Brancheau et al. However, at Some reports have determined the coumarin content of foods and assessed its toxicity (Sproll et al. Thess results are discussed in the context of a strain-specific coumarin metabolism and indicate the need for suitable animal models to assess the toxicity of a given substance in man. , 1992b). , 1996a, b). Coumarin is a component of natural flavourings including cassia, which is widely used in foods and pastries. Studies on human and cynomolgus monkey liver fragments and/or hepatocytes have identified a relative resistance to coumarin toxicity, and this was associated with coumarin 7-hydroxylation, which is the main route of coumarin metabolism. , First-generation anticoagulant rodenticides (eg, warfarin, coumarin) are metabolized within 14 days. Coumarin at a dose of Different anticoagulants have different toxicity levels. The anticoagulant rodenticides are further divided into first- and second-generation based on their toxicity and half-life Many naturally occurring substances, traditionally used in popular medicines around the world, contain the coumarin moiety. This reaction is catalyzed predominantly by CYP1A and CYP2E enzymes (Born et al. For example, the glucoside melilotoside found in sweet clover (Melilotus alba and M. Toxicity of coumarin J Pharmacol Exp Ther. 1. 05mg/lb of body weight. It has been proven to be effective against cucumber mosaic virus (CMV), which is a common pathogen in many horticultural crops. The first group was fed on a diet without any treatment (CON), while the remaining three diets were added with aflatoxin B1 at 0. , 2021). Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 3. There are marked species differences in these responses, with the mouse being particularly susceptible to coumarin-induced Clara cell injury. Coumarin is generally obtained from a natural source, and also can be chemically synthesized. Coumarin is widely used in perfumes, hand soaps, detergents, and lotions at Toxicity of coumarin. Therapeutic Goods Administration Safety review – Moreover, Kluyveromyces marxianus presented the best resistance to substrate toxicity, allowing the biotransformation process even with coumarin concentration up to 1. However, the mechanism underlying these effects remains un coumarin toxicity. In addition, the prospects and outlook for future Genetic toxicology. , 2008; Abraham et al. In a subacute test, auraptene was administered to rats orally in doses of 125–250 mg/kg bw for 28 days, with no observed hematological, histopathological, or biochemical modifications ( Vakili et al. These results suggest possible applications in the management of Alzheimer’s disease. Consuming incredible amounts of cassia cinnamon might increase the risk of coumarin induced hepatotoxicity, but even to reach the recommended TDI of coumarin in cassia, one would need to consume 2g of cinnamon daily for In order to put forward safety considerations and evaluate the impact of coumarin on human body, it was found that coumarin is unlikely to produce hepatotoxicity at normal exposure level. Some are highly toxic with a single feeding, whereas others require multiple feedings to result in toxicity. Even though coumarin itself can be . We have, herein, assessed the data of existing clinical and nonclinical studies as well as those of in Extreme exposure to coumarin, which can result to poisoning, can cause nosebleeds, bleeding gums, bloody urine, ecchymoses, fatigue, shortness of breath, and fluid in lungs. A Round 1. (2006) and the German Federal Institute for Risk Assessment (BfR) (2006a, 2006b Coumarin and its derivatives are plant-derived compounds that exhibit potent insecticidal properties. therapy for lymphedema, several medical . Cinnamon rarely contains enough coumarin to be poisonous, but ingesting a lot of it may make liver issues worse in people who already have them. 1 Single-dose toxicity_____ 13 4. In Practice 12 (4), 174-174 VetMedResource. As a consequence, a huge Coumarin-induced toxicity in the rat liver and mouse lung is dependent on the formation of CE (Lake, 1984, Lake, Walters, and Gangolli, 1989b, Born, Fix, Caudill, & Lehman-McKeeman, 1998). Coumarin is hepatotoxic in rats and mice. Although only somewhat dangerous to humans, coumarin is Eighty-four male New Zealand White rabbits with average body weight 778 ± 65 g were blocked into four groups to evaluate the ability of sodium bentonite and coumarin in alleviating the toxicity of aflatoxin B1. Coumarin is hepatotoxic in rats, but less so in mice. Children eating oatmeal porridge with cinnamon may exceed the TDI with several folds. Label elements Pictogram(s) Signal word Danger Hazard statement(s) H301 Toxic if swalloed. go back to reference Gan J, Qian W, Lin S (2018) Umbelliferone Alleviates Myocardial Scopoletin is a coumarin synthesized by diverse medicinal and edible plants, which plays a vital role as a therapeutic and chemopreventive agent in the treatment of a variety of diseases. Coumarin induced gene mutations in Salmonella typhimurium strain TA100 in the presence, but not in the absence, of exogenous metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or TA1537, with or without S9. Aquatic toxicity studies have shown LC50 values of 56 mg/L for fish and EC50 values of 55 mg/L for Daphnia magna. In especially sensitive persons, even comparatively small quantities of coumarin can cause liver damage, although the effect is usually reversible. officinalis) is an ether of glucose bonded with an ester bond to coumarin. Second-generation anticoagulant rodenticides (eg, bromadiolone, brodifacoum) are more potent, with prolonged toxic effects, requiring 4 weeks of . Therefore, coumarin consumption is regulated, and maximum levels are set for certain foods. Coumarin metabolism, toxicity and carcinogenicity: Relevance for human risk assessment. Coumarin is a simple scaffold widespread in Nature and it can be found in a considerable number of plants as well as in some fungi and bacteria. 2% w:v). P264 Wash Although adverse effect in humans (e. Not Available. Discover how groundbreaking research is turning "undruggable" targets into therapeutic opportunities. 1998 Jun;12(2):91-8. After 2 hr either the cells were used for The rat hepatic toxicity of coumarin and methyl analogues (3-,4-methyl coumarin and 3,4-dimethylcoumarin) has been determined in vivo and in vitro (freshly-isolated cells). represented as an effective pharmacological . Coumarin is usually sold in the form of colourless shiny leaflets or rhombic crystals (Boisde & Meuly, 1993). At that time the SCF reviewed the toxicity of coumarin , in order that the Commission could consider whether the limits for coumarin in food set out in Annex II of the flavourings Directive 88/388/EEC (Council Directive, 1988) needed to be amended. Interactions Drug Interactions . Coumarins have many biological activities and wide clinical applications Reduced food consumption, which reduces body weight and liver damage, is typically the primary outcome associated with long-term exposure to coumarin in rats. Similar Conditions Malabsorption syndromes and sterilisation of the gastrointestinal tract by prolonged antibiotic usage will also result in the depletion of vitamin K-dependent clotting factors 7 . The The multiple effects as well as the ongoing human exposure to coumarin have resulted in a significant research effort focused on understanding the mechanism of coumarin induced toxicity/carcinogenicity and its human relevance. It discusses the mechanisms, risk factors, and clinical implications of coumarin-induced Coumarin is a secondary phytochemical with hepatotoxic and carcinogenic properties. 8 - 12. A single coumarin dose induces hepatocellular necrosis while repeated doses induce only hepatocyte degeneration. The widespread use of coumarin-based anticoagulant rodenticides in most countries of the world and in Ukraine determines the regular occurrence of poisonings among the population. The TDI was based on the potential of liver toxicity and not the cardiovascular effects discussed above. Signs generally reflect blood loss from ruptured blood vessels, including anemia, semisolid masses of blood in the tissues, or bleeding into various areas of the body (the gastrointestinal tract, the eye, the nose, the lungs, Besides, as medicinal candidates a lot of coumarin compounds with strong pharmacological activity and low toxicity and high bioavailability and better curative effects, etc. cause cancer or reproductive toxicity. It is also reported that the toxicity of coumarin is metabolism and species dependent (Born et al. Overall, our previous results indicated that the problem of substrate concentration could be partially solved employing specific strains, specially selected for their resistance to coumarin chronic toxicity: dermal Remarks: combined repeated dose and carcinogenicity Type of information: experimental study Adequacy of study: key study Reliability: 2 (reliable with restrictions) Data source. , determined that a tolerable daily intake (TDI) of coumarin was up to 0. 5, 1 and 2 mmol/L coumarin in 24 h cultured precision-cut male Sprague-Dawley rat, Dunkin-Hartley guinea-pig, While coumarin 14 appears to have the highest toxicity, coumarin 2 had the lowest value of vertical excitation, suggesting that coumarin 2 should be the most toxic compound of group 2. In addition, two new risk assessments of coumarin have been performed by Felter et al. Mol Nutr Food Res 54(2):228–239. Cultures were maintained at 37 in a humidified atmosphere of 5% COZ/95% air. The underlying mechanisms of coumarin-related toxicity have yet to be fully understood (Abraham et al. Measurements of α-AL in these STPs found that the majority did not have quantifiable contents, however, for three STPs concentrations of α-AL were above the LOQ (116–140 ng/g WWB Coumarin Glycosides . Find out the sources, side effects, benefits and precautions of Data available on coumarin absorption, distribution, metabolism, and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. The identification of idiosyncrasies can be crucial not only to protect vulnerable patients, but also to fully exploit coumarin as a pharmaceutical for patients that are not at risk of developing hepatotoxicity and that could greatly benefit from this treatment. It has been used as a flavoring compound. 423-453. In this study, we found that natural coumarin significantly inhibited the growth and development of Spodoptera litura larvae Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. 8 g/L. , 2010 ). Humans metabolize it mainly to 7-hydroxycoumarin, a compound of lower toxicity, and no The mechanism of coumarin-induced tumour formation in rodents is associated with metabolism-mediated, toxicity and it is concluded that exposure to coumarin from food and/or Learn about coumarin, a chemical compound found in some foods and medications that can have serious effects on health when consumed in high amounts. We tested a small library of 18 coumarin derivatives against human invasive breast ductal carcinoma cells with the capacity of each compound to inhibit cell proliferation scored, and the most potent coumarin analogues selected for further studies. Due to these numerous therapeutic advantages, the pharmacodynamics and pharmacokinetics behaviours of coumarin and its derivatives are best understood through interaction studies Coumarin toxicity against M. MeSH terms Coumarins / toxicity* Humans Coumarin and its derivatives are plant-derived compounds that exhibit potent insecticidal properties. The risk of haemorrhage increases with increasing intensity of anticoagulation and overanticoagulation is common. , 1990a, b). However, cytotoxicity at high concentrations was observed [26], [27]. Precautionary statement(s) P201 Obtain special instructions before use. ” There are few studies evaluating the genetic toxicity of natural and synthetic coumarin derivatives in the literature. 99, 100 Other possible reasons include the high liposolubility and photosensitization of some coumarins, Coumarin is a secondary phytochemical with hepatotoxic and carcinogenic properties. Although mice However, high doses of coumarin can affect blood clotting and cause liver toxicity. Further, the increased body weight gains and better-feed conversion in coumarin-supplemented rabbits project the coumarin as a better anti-aflatoxigenic supplement. 4-Methylesculetin was evaluated in vitro and in vivo and all endpoints investigated showed that this synthetic coumarin derivative had no mutagenic or genotoxic effects. In the NGRA for systemic toxicity of both, phenoxyethanol and coumarin, there are several common points that can be categorised as: 1 Viable cells 2. Article CAS PubMed Google Scholar Rangaswami S, Seshadri TR, Venkateswarlu V (1941) The remarkable fluorescence of certain coumarin derivatives. The majority of tests for mutagenic and genotoxic potential Coumarin was banned from market by the Food and Drug Administration (FDA) in 1952, and then, disputes over its toxicity are raised (Egan et al. The mechanisms involve either inhibition of proteins essential for Additionally, although warfarin is no longer used primarily as a rodenticide, several long-acting coumarin derivatives (the so-called superwarfarin anticoagulants, such as brodifacoum, diphenadione, chlorophacinone, and bromadiolone) are used for this purpose and can produce profound and prolonged anticoagulation. Coumarin can adversely affect the digestive, Density: 0. Hamsters and gerbils are resistant to acute coumarin This chapter contains sections titled: Risk from Furocoumarins in Food? An Exposure Assessment Transcriptome Analysis in Benefit–Risk Assessment of Micronutrients and Bioactive Food Components Coumarin, a naturally occurring compound found in various plants, has a rich history of use in traditional medicine. 1-4. PMID: 13377304 No abstract available. Coumarin-induced hepatocellular toxicity in rats involves reactive metabolite formation by CYP1A and CYP2E1 (Born et al. Purpose of the work: to familiarize general practitioners with the biological and toxic effects of 4-hydroxycoumarin derivatives using a separate clinical observation. Download eBook . In addition, we can also hypothesize that coumarin may also induce relevant behavioural Despite the many positive qualities of this spice, most cinnamon varieties have the following drawbacks: Numerous plants, including cinnamon, contain coumarin—a substance that, in high concentrations, can lead to liver damage. Interestingly, intracellular CYP2E1 distribution alters the sensitivity to coumarin-induced hepatocellular toxicity. Case Report: A 73-year-old woman was seen in the Emergency Department complaining of abdominal pain associated with vomiting and diarrhea after she started taking cinnamon supplements for about 1 week. High doses of coumarin by the oral route are known to be associated with liver toxicity in rodents. (1999). Despite the comparatively low amounts of spices consumed, research has revealed that In 2010, Abraham, et al. Download eBook. Switching the tVB moiety from carbon-4 to carbon-3 on the coumarin molecule contributes to a reduction in efficacy by a factor of two. Some people have Meanwhile, some coumarin derivatives have obvious toxic effects in rodents and the toxicity of coumarins in different animals and organs are significantly different, and toxic reactions occurred mainly in the coumarin metabolism after high dose oral administration. As a pharmaceutical, coumarin has been used in diverse applications with a wide variety of dosing regimens. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 In vivo, coumarin toxicity was indicated by increased plasma ALAT, ASAT, and GGT levels, primarily at the highest dose level of 200 mg/kg b. 25 ppm diet. Treatment with coumarin oral anticoagulants, such as warfarin, is effective antithrombotic therapy, but patients treated with these drugs are at significant risk of bleeding. It has been Abraham K, Wöhrlin F, Lindtner O, Heinemeyer G, Lampen A (2010) Toxicology and risk assessment of coumarin: focus on human data. The results of this study indicate that the chemical structures of coumarins play an important role in the prevention of liver toxicity. The researchers have meticulously explored the toxicological mechanisms of coumarin, revealing its potential as a natural and In vivo, coumarin toxicity was indicated by increased plasma ALAT, ASAT, and GGT levels, primarily at the highest dose level of 200 mg/kg b. On the other hand, adding a methoxy group to the meta position boosts the effect to a level close to that of the well-recognized antitumor drug Meanwhile, some coumarin derivatives have obvious toxic effects in rodents and the toxicity of coumarins in different animals and organs are significantly different, and toxic reactions occurred mainly in the coumarin metabolism after high dose oral administration. Exposure to the general public is through the diet and from its use as a perfume raw material in personal care products. 07 mg/kg. Reviewer 1 Report The study on coumarin and its derivatives as potential insecticides, and their effect on Spodoptera litura larvae, is both fascinating and significant in the realm of pest control and agriculture. Algal respiration is inhibited at laboratory concentrations of 50 mmol/L. 4 g of coumarin, which means 1 teaspoon of [cassia cinnamon] powder would contain around 5. It was also suggested that species differences due to different metabolic patterns in model animals should be carefully considered when assessing coumarin toxicity, in order to provide reference Coumarin target organ toxicity and carcinogenic response is species-specific, non-genotoxic, and is directly related to specific metabolism/detoxification capabilities following bolus oral exposure. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. No toxicity has been reported following dermal Coumarin exhibits low environmental toxicity. This information Coumarins. The identification of idi osyncrasies can be crucial not only to protect . Coumarin is an important class of natural organic compounds, which widely exists in a variety of plants and microorganisms. Pathways Not Available Pharmacogenomic Effects/ADRs . An efficient method for routine analysis of (a) Coumarin is the chemical 1,2-benzopyrone, C9H6O2. 1 mg/kg body Coumarin is a flavouring substance which is contained in relatively high concentrations in cinnamon varieties collectively known as "Cassia cinnamon". 99, 100 Other possible reasons include the high liposolubility and photosensitization of some coumarins, certainly, Coumarin was well tolerated, except that it resulted in serologic evidence of liver toxicity in 6 percent of the women. It yields the toxicant dicoumarol when exposed to specific molds The study further showed that the coumarins formed hydrogen bonds with LYS293 on the enzyme to lower the binding affinity for the saccharose in silico. It is possible that heavy consumption of the cinnamon included in cookies, tea, and other cinnamon rich foods could exceed the TDI, making it important to pay careful attention to the amount of cinnamon taken in food ( Abraham et al. We have, herein, assessed the data of existing clinical and nonclinical studies as well as those of in silico models for humans in order to shed more light on this association. Its uses include as a flavoring agent, fragrance enhancer, and odor-masking additive. CYPs have an N-terminal hydrophobic group, which localizes the nascent protein to the ER membrane. Reference Reference Type: review article or handbook Title: No information Author: HSDB Year: 2003 Bibliographic source: HSDB (Hazardous Substances The general toxic effects of coumarin, as well as coumarin hepatotoxicity were found to be less in DBA/2J mice than in CH3/HeJ mice. Ceylon cinnamon (Cinnamomum verum), known as “true” cinnamon, grows primarily in Sri Lanka. As such we developed a mitochondria-targeting, fluorescence-based ratiometric probe using a boronate group for ONOO − recognition and Hepatotoxicity associated with food-derived coumarin occurs occasionally in humans. Return to reference 5 Coumarin is a naturally occurring sweet-smelling benzopyrone that may be extracted from plants or synthesized for commercial uses. This section will discuss toxicants that are derived from coumarin compounds in plants. Wird es in größeren Mengen eingenommen, ist es giftig. Reversal ca Management of warfarin (coumarin) overdose Blood Rev. The toxicity of these 1 Basic Medicine College, Chifeng University, Chifeng, China; 2 Inner Mongolia Key Laboratory of Human Genetic Disease Research, Chifeng University, Chifeng, China; 3 Key Laboratory of Mechanism and Evaluation of Chinese and Mongolian Pharmacy at Chifeng University, Chifeng University, Chifeng, China; Scopoletin is a coumarin synthesized by Abstract Coumarins possess a wide array of therapeutic capabilities, but often with unclear mechanism of action. Cinnamon is a spice that comes from the dried bark of various species of Cinnamomum trees. 5 Analysis Coumarin can be determined in vanilla extract by a photometric method, reading the absorbance or transmittance at 490 nm, and comparing against a standard (AOAC Coumarin is a benzopyranone derivative with potential activities. In the present study, we report an in vivo toxicity evaluation of a small series of coumarin (compounds 1–4) and sulfamide (5–9)-based CAIs on 1–5 dpf zebrafish larvae. 3 Relative Exposure_____ 22 Coumarin is a naturally occurring component of a number of food products; including, but not limited to, Ceylon cinnamon, cassia cinnamon and tonka beans. Table 3. Umbelliferone disrupts viral RNA and protein synthesis, significantly reducing the replication of The target organs for coumarin toxicity are primarily the liver in rats and the liver and lung in mice. , 2017 ). , it was determined that coumarin was well tolerated at the applied doses (600–5000 mgs) and it was thought that nausea, which was determined as a common side effect, was The metabolism, toxicity and results of tests for carcinogenicity have been reviewed with respect to the safety for humans of coumarin present in foodstuffs and from fragrance use in cosmetic products. Coumarin is a naturally occurring benzo-α-pyrone compound that is most often used as a fragrance ingredient, where it functions as a fragrance, as a fragrance enhancer, and as a stabilizer. Coumarin is often found in tobacco products and artificial vanilla substitutes, though it has been banned as a food additive in numerous countries since the mid-20th century because it is moderately toxic to the liver and kidneys, with an LD 50 of 275 mg/kg - low compared to related compounds. We reviewed and evaluated the scientific evidence on the carcinogenicity of coumari Cancer Hazard Identification Integrating Human Variability: The Coumarin is one such natural compound that is a potential drug candidate owing to its properties of stability, solubility, and low toxicity. Cinnamon, via coumarin, can cause liver toxicity. G Lake , in Food and Chemical Toxicology , 1999 In vitro studies with short-term rat hepatocyte cultures support in vivo findings that dihydrocoumarin, 3,4-dimethylcoumarin and 3-, 4- and 6-methylcoumarin are all less toxic than coumarin ( Fentem et al. Coumarins are abundant in nature Some coumarin-related derivatives, including osthole, daphnoretin, coumarin, byakangelicin, and 7-hydroxycoumarin (Fig. J Biol Response Mod 8:116–121 PubMed. Coumarin-based antifungal azoles had been further investigated by Elias and co-workers, who, in 2019, developed a series of 11 coumarins conjugated with 1,2,4-triazole and imidazole motifs . G. Unlock the secrets to drugging the undruggable. By using the bench mark dose approach we re-assessed coumarin toxicity and esta The second important pathway involved in coumarin metabolism and toxicity is epoxidation at the 3,4-double bond. The dose and duration of cinnamon supplementation in a meta-analysis included in this review did not exceed the daily tolerable coumarin intake. Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Proc Indian Acad Sci Sect A 13(4 Moreover, these compounds had proven to be safe after in vitro toxicity, in vivo acute oral toxicity and behavioral studies. The toxicology of coumarin merits attention because it exhibits marked species differences in both metabolism and hepatotoxicity (Lake, 1999). Overall, toxicity profiles, toxicity class, and LD50 values showed comparatively lower toxicity for CDs, indicating their suitability as antidiabetic agents at higher dosages (Table S2). Toxicity of coumarin. This allowed the derivation of a tolerable daily intake (TDI) for the first time, and a value of 0. wt. The manifestation of coumarin-induced hepatocellular toxicity may differ and depends on the frequency of administration to rats. , 1992b ; Fernyhough et al. Toxicity, physicochemical and drug-likeness profiles of coumarin derivatives. H351 Suspected of causing cancer. This behavior is consistent in both the functionals. 4 Toxicology _____ 13 4. The polymorphism of CYP2A6 is rather prevalent in the Japanese population, and the non-wild (poor metabolizer) types were reportedly present in Both contain coumarin, though the fake stuff has greater concentrations than the Sri Lankan variety (1% in cassia and only about 0. TheIARCconcludedthatsinceepi- demiological data relevant to the carcinogenicity of coumarin were unavailable and animal carcinogenicity data on coumarin are incon- Another coumarin, umbelliferone (7-hydroxycoumarin), has been found to exhibit antiviral activity (Gliszczyńska and Brodelius, 2012). Reference 5. 2. An efficient method for routine analysis of Moreover, the dose-response relationships for coumarin-induced toxicity and carcinogenicity are non-linear, with tumour formation only being observed at high doses which are associated with hepatic and pulmonary toxicity. The Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency maintains this list in its role as lead agency for implementing Proposition 65. Cassia cinnamon (Cinnamomum PDF | On Sep 30, 2015, Maria João Matos and others published Coumarins — An Important Class of Phytochemicals | Find, read and cite all the research you need on ResearchGate Internal concentrations (plasma C max) were estimated using a physiologically based kinetic model for dermally applied coumarin. These Download Citation | Umbelliferon: a review of its pharmacology, toxicity and pharmacokinetics | Coumarin, a plant secondary metabolite, has various pharmacological activities, including Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes: Comparison with dihydrocoumarin and other coumarin metabolites. There are numerous evidences showing its inhibitory role against infection of various viruses such as HIV, Influenza, Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16). References To elucidate the coumarin degradation mechanism by consortium XDS-7, it was inoculated (5%, v/v) into 100 mL of MSM under three conditions: (i) G: MSM with 100 mg L −1 glucose; (ii) T: MSM with 100 mg L −1 coumarin (2 mL coumarin-methanol stock solutions); (iii) M: MSM with 2 mL methanol (no coumarin). Frontiers reserves the right to guide an out Coumarin is a naturally occurring flavouring substance in cinnamon and many other plants. 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