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PubMed2001

Azole-linked coumarin dyes as fluorescence probes of domain-forming polymers.

The binding of 7-aminocoumarins, substituted in the 3-position with heterocyclic benzimidazole or benzothiazole groups by domain-forming polymers in water has been studied. The acrylic polyelectrolyte, poly(methacrylic) acid (PMAA) was used as a solubilizing agent for coumarin dyes 6, 7, and 30 in water. The acid-base properties of these bound coumarin dyes were monitored spectroscopically on titration of aqueous solutions. Alterations in the fluorescence wavelength and intensity, quantum yields, lifetimes, and polarization are consistent with the preferential binding of the dyes in compact hydrophobic domains that form at a pH regime in which the polymer is in its protonated (uncharged) state. In this pH range (<4.0), coumarins 7 and 30 are bound as monocations, whereas coumarin 6 remains in its neutral form. Reduced quantum yields and lifetimes of fluorescence for cationic coumarins can be understood in terms of the imposition of a low-lying electron transfer state, an example of a twisted intramolecular charge transfer (TICT) intermediate. Effects of polymer microenvironment on the rate of TICT state decay (a reverse electron transfer) are observed. Coumarins of the azole type may find use as fluoroprobes of the microenvironments of proteins and other biological macromolecules and as agents for pH sensing.

Benzimidazoles↗
PubMed2004

Coumarin tags for improved analysis of peptides by MALDI-TOF MS and MS/MS. 1. Enhancement in MALDI MS signal intensities.

The goal of this study was the development of N-terminal tags to improve peptide identification using high-throughput MALDI-TOF MS and MS/MS. The proposed tags, commercially available fluorescent derivatives of coumarin, can be advantageous for peptide analysis in both MS and MS/MS modes. This paper, part 1, will focus on the influence of derivatization on the intensities of MALDI-TOF MS signals of peptides. Labeling peptides with tags containing the coumarin core was found to enhance the intensities of peptide peaks (in some cases over 40-fold) in MALDI-TOF MS using CHCA and 2,5-DHAP matrixes. The signal enhancement was found to be peptide- and matrix-dependent, being the most pronounced for hydrophilic peptides. No correlation was found between the UV absorptivity of the tags at the excitation wavelengths typical for UV-MALDI and the magnitude of the signal enhancement. Interestingly, peptides labeled with Alexa Fluor 350, a coumarin derivative containing a sulfo group (i.e., bearing strong negative charge), showed a 5-15-fold increase in intensity of MALDI MS signal in the positive ion mode, relative to the underivatized peptides, when 2,5-DHAP was used as the matrix. The Alexa Fluor 350 tag yielded a significantly higher signal relative to that for the CAF tag, likely due to the increased hydrophobicity of the coumarin structure. With 2,5-DHB, a decrease of MALDI MS signal was observed for all coumarin-labeled peptides, again relative to the unlabeled species. These findings support the hypothesis that derivatization with coumarin, a relatively hydrophobic structure, improves incorporation of hydrophilic peptides into hydrophobic MALDI matrixes, such as CHCA and 2,5-DHAP.

Amino Acid Sequence↗
PubMed1982

Mechanism of coumarin action: sensitivity of vitamin K metabolizing enzymes of normal and warfarin-resistant rat liver.

The in vitro effects of two coumarin anticoagulants, warfarin and difenacoum, on rat liver microsomal vitamin K dependent carboxylase, vitamin K epoxidase, vitamin K epoxide reductase, and cytosolic vitamin K reductase (DT-diaphorase) from the livers of normal and a warfarin-resistant strain of rats have been determined. Millimolar concentrations of both coumarins are required to inhibit the carboxylase and epoxidase activities in both strains of rats. Sensitivity of DT-diaphorase to coumarin inhibition differs when a soluble or liposomal-associated substrate is used, but the diaphorases isolated from both strains of rats have comparable sensitivity. The anticoagulant difenacoum is an effective rodenticide in the warfarin-resistant strain of rats, and the only enzyme studied from warfarin-resistant rat liver that demonstrated a significant differential inhibition by the two coumarins used was the vitamin K epoxide reductase. This enzyme also showed the greatest sensitivity to coumarin inhibition among the enzymes studied. These results support the hypothesis that the physiologically important site of action of coumarin anticoagulants is the vitamin K epoxide reductase.

4-Hydroxycoumarins↗
PubMed2006

Comparative analyses of bioactive Mammea coumarins from seven parts of Mammea americana by HPLC-PDA with LC-MS.

Mammea americana L. is tropical plant in the Clusiaceae family that bears edible fruit. Mammea coumarins are isoprenylated derivatives of the lactones of the 2-hydroxy-Z-cinnamic acids that are bioactive and have limited distribution in three Clusiaceae genera. Qualitative and quantitative analyses were performed to determine the distribution of mammea coumarins in the seed nucleus, seed coat, fruit flesh, fruit skin, leaf, stem, and root of M. americana using high-performance liquid chromatography-photodiode array detector (HPLC-PDA) and liquid chromatography-mass spectrometry (LC-MS). Ten major mammea coumarins, mammea E/BD (1), mammea E/BC (2), mammea E/BA (3), mammea E/BB (4), mammea B/BA hydroxycyclo F (5), mammea B/BD (6), mammea B/BC (7), mammea B/BA (8), mammea B/BB (9), and mammea B/BA cyclo F (10), were isolated and identified from the seed nucleus of M. americana and employed as standards. The HPLC-PDA method was validated with respect to sensitivity, linearity, recovery, accuracy, and precision. The total content (w/w %) of the 10 major mammea coumarins in M. americana was determined to be highest in the root (0.75%), followed by the leaf (0.64%), seed nucleus (0.48%), fruit skin (0.11%), stem (0.08%), seed coat (0.02%), and fruit flesh (<0.01%). The leaf and seed nucleus are rich and sustainable natural sources of mammea coumarins. Additionally, the described HPLC-PDA and LC-MS methods are sensitive and accurate and can be applied to the analysis of mammea coumarins in other samples.

Chromatography, High Pressure Liquid↗
PubMed2000

Chemical constituents of Clausena excavata: isolation and structure elucidation of novel furanone-coumarins with inhibitory effects for tumor-promotion.

A study of the chemical constituents of the leaves of Clausena excavata cultivated in a greenhouse led to the isolation and identification of 10 new furanone-coumarins named clauslactones A (1), B (2), C (3), D (4), E (5), F (6), G (7), H (8), I (9), and J (10), together with a known carbazole, clauszoline M, and a coumarin, umbelliferone. The new coumarins contain a C(10) terpenoid side chain with a furanone (gamma-lactone) moiety. Further, in clauslactones A-D (1-4), the terpenoid side chain was shown to be linked to the 7,8-dioxygenated coumarin skeleton through a 1, 4-dioxane ring system. This is the first example of coumarins with these structural characteristics in nature. These furanone-coumarins were found to exhibit inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus early antigen activation in Raji cells.

Anticarcinogenic Agents↗
PubMed2003

A randomized trial assessing the effect of coumarins started before coronary angioplasty on restenosis: results of the 6-month angiographic substudy of the Balloon Angioplasty and Anticoagulation Study (BAAS).

BACKGROUND: Thrombus formation during coronary angioplasty may play a role in the restenosis process. METHODS: The effect of pretreatment with coumarins on 6-month angiographic outcome was studied. In addition, the effect of "optimal" anticoagulation, defined as an international normalized ratio >70% of the follow-up time in the target range, was studied. A total of 261 patients were assigned to aspirin alone (ASA group) and 270 patients to aspirin plus coumarins started 1 week before the procedure (coumarin group). RESULTS: The mean international normalized ratio was 2.7 +/- 1.2 at the start of the procedure and 3.1 +/- 0.5 during follow up. Quantitative coronary analysis was performed on 301 lesions in the ASA group and of 297 lesions in the coumarin group. At 6 months, the minimal luminal diameter was similar in the ASA and coumarin groups. Optimal anticoagulation, however, was an independent predictor of a larger minimal luminal diameter at follow up (P =.01). CONCLUSION: Overall, coumarins do not improve angiographic outcome 6 months after coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed2000

Effect of cigarette smoking on coumarin metabolism in humans.

Extant data, mostly from studies in vitro, suggest that coumarin and nicotine are both metabolized by CYP2A6, a cytochrome P450 isozyme. In order to investigate this issue further, the activity of this enzyme in vivo was measured in 37 non-smokers and 37 smokers using coumarin (2.0 mg, PO) as the metabolic probe. The percentage of coumarin metabolized to 7-hydroxycoumarin in 8 h was measured in urine by high-pressure liquid chromatography. There was more than 10-fold variability in coumarin metabolism in both groups. Coumarin metabolism was significantly reduced in smokers (46.6 +/- 4.4%) as compared to non-smokers (66.4 +/- 3.5%; p < or = .001). The results support previous in vitro findings that both coumarin and nicotine are metabolized, at least in part, by a common pathway, which most likely is CYP2A6.

Administration, Oral↗
PubMed1997

Inhibitory effects of naturally occurring coumarins on the metabolic activation of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured mouse keratinocytes.

Several naturally occurring coumarins to which humans are routinely exposed have been previously found to be potent inhibitors and inactivators of cytochrome P450 (P450) 1A1-mediated monooxygenase in both murine hepatic microsomes and in a reconstituted system using purified human P450 1A1 [Cai et al. (1993) Chem. Res. Toxicol., 6, 872-879 and Cai et al. (1996) Chem. Res. Toxicol., 9, 729-736]. In the present study, several of these coumarins were investigated for their inhibitory effects on the metabolism and metabolic activation of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in cultured mouse keratinocytes. Initial analysis of B[a]P metabolism in cultured keratinocytes showed that imperatorin, isoimperatorin, coriandrin, and bergamottin, at concentrations of 2 nM equal with B[a]P, reduced the formation of water-soluble metabolites of B[a]P by 33% to 57%. Bergamottin and coriandrin were the most potent inhibitors of the compounds examined. HPLC analysis of organic solvent-soluble metabolites of B[a]P indicated that all the coumarins tested significantly reduced the formation of individual B[a]P metabolites (including phenols, diols and tetraols). However, the greatest effect was on the formation of B[a]P tetraols. Additional experiments determined the ability of selected coumarins to block covalent binding of B[a]P and DMBA to DNA in keratinocytes. Bergamottin preferentially inhibited the binding of B[a]P to DNA by 56%, while coriandrin preferentially inhibited the binding of DMBA to DNA by 48%. Notably, analysis of individual DNA adducts formed from B[a]P and DMBA indicated that both bergamottin and coriandrin specifically inhibited the formation of anti diol-epoxide DNA adducts derived from both hydrocarbons. The preferential inhibitory effect of bergamottin and coriandrin on the formation of anti diol-epoxide adducts derived from DMBA was further confirmed by separation of anti- and syn-diol-epoxide-DNA adducts using immobilized boronate chromatography. The current study demonstrates that certain naturally occurring coumarins inhibited metabolic activation of B[a]P and DMBA in cultured mouse keratinocytes and specifically inhibited the formation of DNA adducts derived from the anti diol-epoxide diastereomers from either hydrocarbon. The current data also suggest that certain naturally occurring coumarins may possess anticarcinogenic activity toward polycyclic aromatic hydrocarbons.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Naturally occurring coumarins inhibit 7,12-dimethylbenz[a]anthracene DNA adduct formation in mouse mammary gland.

Naturally occurring coumarins (NOCs) are anti-carcinogenic in the mouse skin model. To characterize the chemopreventive potential of NOCs against breast cancer, we first examined their effects on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation in mouse mammary gland. We hypothesized that those NOCs that both inhibited cytochrome P450 1A1/1B1 and induced hepatic glutathione S-transferases (GSTs) would be the most effective in blocking DMBA-DNA adduct formation in mouse mammary gland. To address this hypothesis, simple coumarins (e.g. coumarin and limettin, which induced mouse hepatic GSTs but had little effect on P4501A1/1B1) and linear furanocoumarins (e.g. imperatorin and isopimpinellin, which induced hepatic GSTs and were potent inhibitors of P4501A1/1B1) were compared. Mice were pretreated with NOCs (150 mg/kg body wt, by gavage) prior to either a single dose of DMBA (50 microg) or multiple doses of DMBA (20 microg daily for 3 and 6 weeks). Mammary DMBA-DNA adduct formation was quantitated by the nuclease P1-enhanced 32P-postlabeling assay. With the single dose of DMBA, coumarin, limettin, imperatorin and isopimpinellin inhibited DMBA-DNA adduct formation by 50, 41, 79 and 88%, respectively. Coumarin, limettin and imperatorin blocked DMBA-DNA adduct formation by 36, 60, and 66% at 3 weeks, and by 0, 49 and 55% at 6 weeks of DMBA dosing, respectively. In a 6 week dose-response study of select NOCs and 7,8-benzoflavone (a potent P4501 inhibitor that had little effect on GSTs), DMBA-DNA adduct formation was inhibited by 0, 43 and 24% in the limettin groups; by 26, 26 and 69% in the isopimpinellin groups; and by 80, 96 and 97% in the 7,8- benzoflavone groups at 35, 70 and 150 mg/kg, respectively. Taken together, these results suggest that linear furanocoumarins had a greater inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared with simple coumarins, and that the predominant effect may be P4501 inhibition.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

The influence of cyclo-oxygenase specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant coumarine users.

BACKGROUND: Concomitant use of coumarines and non-steroidal anti-inflammatory drugs (NSAIDs) may induce bleeding complications, due to the inhibition of both coagulant factors and platelet function. Unlike non-selective NSAIDs, cyclo-oxygenase-2 (COX-2)-selective NSAIDs interfere very little with platelet aggregation. AIM: To determine whether COX-2-selective NSAIDs are associated with less bleeding complications in coumarine users, compared with non-selective NSAIDs. DESIGN: Prospective, nested case-control study. METHODS: We studied concomitant coumarine and NSAID users over two years. Patients with bleeding (cases), and frequency-matched patients without bleeding (controls), were sent questionnaires regarding possible risk factors for bleeding. International normalized ratio (INR) values were recorded. Univariate and multivariate analyses were used to detect factors contributing to bleeding. RESULTS: There were 1491 reported bleeds. NSAIDs were involved in 14.8%; 3.9% involving COX-2-selective NSAIDs. In non-bleeders, 2601 prescriptions with a coumarine/NSAID combination were detected; 9.7% were COX-2-selective. Adjusted ORs (95% CI) for a bleeding complication were 3.07 (1.18-8.03) for non-selective NSAID use, 3.01 (1.42-6.37) for NSAID use > 1 month, and 1.89 (1.03-3.49) for INR > or = 4.0. DISCUSSION: In coumarine users, COX-2-selective NSAIDs are associated with less bleeding complications than non-selective NSAIDs are. Duration of NSAID use, as well as intensity of coumarine treatment, plays an important additional role. When the coumarine-NSAID combination is inevitable in an individual patient, a COX-2-selective NSAID may be preferred, with careful monitoring of the INR.

Aged↗
PubMed2006

Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: a toxicogenomics approach.

Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro system with improved metabolic competence enhances the predictability for coumarin-induced in vivo toxicity by using a toxicogenomics approach. Therefore, primary rat hepatocytes were cultured in sandwich configuration in medium containing a mixture of low concentrations of P450 inducers, phenobarbital, dexamethasone, and beta-naphthoflavone. The toxicogenomics approach used enabled comparison of similar mechanistic end-points at the molecular level between in vitro and in vivo conditions, namely, compound-induced changes in multiple genes and signaling pathways. Toxicant-induced cytotoxic effects and gene expression profiles observed in hepatocytes cultured in modified medium and hepatocytes cultured in standard medium (without inducers) were compared with results from a rat in vivo study. Coumarin was used as a model compound because its toxicity depends on bioactivation by P450 enzymes. Metabolism of coumarin toward active metabolites, coumarin-induced cytotoxicity, and gene expression modulation were more pronounced in hepatocytes cultured in modified medium compared with hepatocytes cultured in standard medium. In addition, more genes and biological pathways were similarly affected by coumarin in hepatocytes cultured in modified medium and in vivo. In conclusion, these experiments showed that for coumarin-induced toxicity, sandwich-cultured hepatocytes maintained in modified medium better represent the situation in vivo compared with hepatocytes cultured in standard medium.

Alanine Transaminase↗
PubMed2000

Photodynamic treatment of pooled coumarin plasma for external quality assessment of the prothrombin time.

AIMS: To determine the conditions of photodynamic inactivation of vesicular stomatitis virus (VSV) added to pooled coumarin plasma and the effects of the photodynamic treatment on the prothrombin times and international normalised ratio (INR) in a Netherlands national external quality assessment scheme. METHODS: Pooled coumarin plasma samples were illuminated with visible light in the presence of 1 microM methylene blue. Inactivation conditions for VSV in pooled coumarin plasma were determined using an end point dilution assay. Plasma illuminated for 20 minutes was mixed with red blood cells and mailed to participants of the Netherlands external quality assessment (EQA) scheme. Prothrombin times and INRs were determined with various thromboplastin reagents. RESULTS: Photodynamic treatment using 1 microM methylene blue and 700 W/m2 caused 4.7 log inactivation of VSV in pooled coumarin plasma. Fibrinogen and coagulation factors II, V, VII, and X were decreased slightly by the treatment. These conditions caused prolongation of the prothrombin time in EQA surveys. The magnitude of the effect was different for various thromboplastin reagents. The increase of the INR was negligible when measured with the Thrombotest reagent. With other reagents, an approximately 5-16% increase of the INR was observed. Interlaboratory variation of the INR was not affected by photodynamic treatment. CONCLUSIONS: Photodynamic treatment of pooled coumarin plasma is very effective for the inactivation of some enveloped viruses such as VSV, but has only a limited effect on the prothrombin time and INR. Photodynamic treatment can be used to improve the viral safety of coumarin plasma for EQA of the prothrombin time and INR.

Coumarins↗
PubMed2000

Effect of coumarins started before coronary angioplasty on acute complications and long-term follow-up: a randomized trial.

BACKGROUND: Coronary angioplasty frequently creates a thrombogenic surface, with subsequent mural thrombosis that may lead to acute complications and possibly stimulates the development of restenosis. Whether coumarins can prevent these complications is unclear. The objective of this open, randomized trial was to assess the clinical effect of coumarins started before coronary angioplasty and continued for 6 months. METHODS AND RESULTS: Before coronary angioplasty, 530 patients were randomly assigned to aspirin plus coumarins and 528 patients to aspirin alone. At the start of the angioplasty, the mean international normalized ratio was 2.7+/-1.1; during follow-up, it was 3.0+/-1.1. At 30 days, the composite end point of death, myocardial infarction, target-lesion revascularization, and stroke was observed in 18 patients (3.4%) treated with aspirin plus coumarin compared with 34 patients (6.4%) treated with aspirin alone (relative risk, 0.53; 95% CI, 0.30 to 0.92). At 1 year, these figures were 14.3% and 20.3%, respectively (relative risk, 0.71; 95% CI, 0.54 to 0.93). The incidence of major bleeding and false aneurysm during hospitalization was 3.2% and 1.0%, respectively (relative risk, 3.39; 95% CI, 1.26 to 9.11). The benefit of coumarins was observed in both stented and nonstented patients. CONCLUSIONS: Coumarins in addition to aspirin started before PTCA and continued for 6 months was more effective than aspirin alone in the prevention of acute and late complications after coronary angioplasty. This benefit was accompanied by a small but significant increase in bleeding complications.

Aged↗
PubMedDate not supplied

Cataract surgery under systemic anticoagulant therapy with coumarin.

PURPOSE: To evaluate clinical outcome of cataract surgery under systemic anticoagulant therapy using coumarin. METHODS: This clinical interventional comparative nonrandomized study included 441 patients (441 eyes) consecutively undergoing standard phacoemulsification with clear cornea incision and topical anesthesia. The study group consisted of 21 (4.8%) patients for whom systemic coumarin therapy was continued despite surgery. The control group included 420 patients without anticoagulant coumarin therapy prior to surgery. Study group and control group did not vary significantly in age, preoperative visual acuity, axial length, refractive error, preoperative intraocular pressure, or surgeon. RESULTS: Frequency of intraoperative or postoperative hemorrhages, intraoperative complications such as posterior capsule rupture, postoperative visual acuity, and intraocular pressure did no vary significantly (p>0.30) between study group and control group. CONCLUSIONS: For patients under systemic coumarin therapy, the rate of surgical complications may not markedly be increased compared to patients without coumarin therapy, when standard phacoemulsification with clear cornea incisions is performed with topical anesthesia. Systemic coumarin therapy does not have to be stopped prior to cataract surgery.

Aged↗
PubMed2001

Determination of coumarin metabolism in Turkish population.

Cytochrome P450 2A6 is an important human hepatic P450 which activates precarcinogens and oxidizes some drug constituents such as coumarin, halothane, and the major nicotine C-oxidase. Genetic polymorphism exists in the CYP2A6 gene. CYP2A6*1 (wild type) is responsible for the 7-hydroxylation of coumarin. The point mutation (T to A) in codon 160 leads to a single amino acid substitution (Leu to His) and the resulting protein, CYP2A*2 is unable to 7-hydroxylate coumarin. Gene conversion in exons 3, 6, and 8 between the CYP2A6 and the CYP2A7 genes creates another variant, CYP2A6*3. In this study, healthy male and female Turkish volunteers (n = 50) were administered 2 mg coumarin, and urine samples were analyzed for their content of the coumarin metabolite, 7-hydroxycoumarin (7OHC), by high-performance liquid chromatography (HPLC). Genetic polymorphism for CYP2A6 was detected by using two-step polymerase chain reaction (PCR) to identify CYP2A6*1, CYP2A6*2, and CYP2A6*3 in 13 of these subjects. The percentage of the dose excreted of total 7OHC in relation to CYP2A6 genotype and excretion of nicotine/cotinine was also evaluated to demonstrate the role of CYP2A6 in nicotine metabolism. The majority of Turkish subjects (68%) excreted less than 60% of the 2-mg dose as coumarin metabolite. The allelic frequencies were detected as 0.88 for CYP2A6*1 allele; 0.12 for CYP2A6*3 allele in 13 individuals. No heterozygous and homozygous individuals were identified for the CYP2A6*2 allelic variant. Phenotyping and genotyping for drug metabolizing enzymes are of great importance in studies correlating precarcinogen activation or drug metabolism to the CYP2A6 genotype in smoking behavior when populations are investigated.

Adult↗
PubMed2001

In utero exposure to coumarins and cognition at 8 to 14 years old.

OBJECTIVE: To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero. BACKGROUND: Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood. METHODS: The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child. RESULTS: No differences in mean IQ were found between the exposed and nonexposed cohort (mean difference: -1.1; 95% confidence interval [CI]: -3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests for educational achievement, exposed children as a group performed as well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0). CONCLUSION: Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy.

Adolescent↗
PubMed2006

Synthetic and natural coumarins as antioxidants.

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogs. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their antioxidant effects were extensively examined. In this review, plant derived coumarins and their synthetic analogs will be systematically evaluated based on their plant origin, structure-activity relationship and antioxidant efficacy. Owing their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action has not yet been fully understood and the correlation of effects with chemical structure is not conclusive at the moment. It is the objective of this review will be to summarize experimental data for different coumarins used as antioxidant agents, because promising data have been reported for a series of these agents. In addition, their ability to bind metal ions represents an additional means of modulating their pharmacological responses.

Animals↗
PubMed1994

Metabolism of [3-14C] coumarin by human liver microsomes.

1. The metabolism of 50 microM [3-14C] coumarin has been studied in a panel of 12 human liver microsomal samples of known P450 isoenzyme profile. 2. [3-14C] coumarin was metabolized by human liver microsomes to various polar products including 3-, 4- and 7-hydroxycoumarins (3-HC, 4-HC and 7-HC) 6,7-dihydroxycoumarin (6,7-DiHC), o-coumaric acid (o-CA), o-hydroxyphenyl-acetaldehyde (o-HPA), o-hydroxyphenylethanol (o-HPE), o-hydroxyphenylacetic acid (o-HPAA) and o-hydroxyphenylpropionic acid (o-HPPA) and to product(s) that bind covalently to microsomal proteins. 3. For all 12 subjects, mean rates of [3-14C] coumarin metabolism to total polar products (metabolism to all products except product(s) covalently bound to microsomal proteins), 7-HC, the 3-hydroxylation pathway (sum of 3-HC, o-HPA, o-HPE and o-HPAA), o-HPPA, 6,7-DiHC and covalent binding were 1420, 1230, 73.8, 52.5, 9.5 and 4.8 pmol/min/mg protein respectively. 4. Marked interindividual differences in [3-14C] coumarin metabolism to total polar products (30-fold variation) and 7-HC (2250-fold variation) were observed. 5. Good correlations were observed between [3-14C] coumarin metabolism and total polar products, 7-HC, o-HPPA and 6,7-DiHC, but not to 3-hydroxylation pathway products and levels of 2A6 and 2B6 in human liver microsomes. 6. [3-14C] coumarin metabolism to any polar products did not correlate with levels of 1A2, 2C8, 2C9, 2E1, 3A3/4 and 4A1 in human liver microsomes.

Biotransformation↗