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PubMed2001

Inhibition of concanavalin A-induced mice hepatitis by coumarin derivatives.

The effects of coumarin derivatives, osthole, imperatorin, Pd-Ia, Pd-II and Pd-III, on mice concanavalin A (Con A) (0.2 mg/mouse, i.v.)-induced hepatitis were studied. At the dose of 200 mg/kg (i.p.), these coumarins inhibited more than 90% of the Con A-induced elevation of plasma alanine aminotransferase activity, but glycyrrhizin (200 mg/kg, i.p.) caused only 45% inhibition. At the dose of 100 mg/kg (i.p.), osthole produced the strongest inhibition among these coumarins. The inhibitory activity of osthole is lost when its 7-methoxy group is replaced by a 7-hydroxy group to form osthenol. The present results showed that coumarin derivatives inhibited Con A-induced hepatitis, with osthole being the most inhibitory.

Alanine Transaminase↗

PubMedDate not supplied

Natural inhibitors of germination and growth, VII synthesis of ribulosebisphosphate carboxylase in darkness and its inhibition by coumarin.

Cress (Lepidium sativum) seeds were germinated in darkness. Seedlings were investigated for soluble proteins by SDS-PAGE. Two proteins were identified by microsequencing: the small subunit of ribulosebisphosphate carboxylase (SSU) and the alpha subunit of the storage protein cruciferin. Net synthesis of small and large subunits of ribulosebisphosphate carboxylase (SSU and LSU) was investigated by Western blot. Net synthesis of both subunits was inhibited by coumarin. To the contrary, net synthesis of cruciferin was increased by coumarin. With specific cDNA probes, we determined steady state levels of the corresponding mRNAs (rbcS mRNA for SSU, rbcL mRNA for LSU). Both mRNAs can be detected in dry seeds; their amount increases during germination in the dark. Incubation with coumarin inhibits this increase. Inhibition of development by coumarin on the level of transcription is discussed.

Amino Acid Sequence↗

PubMedDate not supplied

Investigations of the solvent polarity effect on the photophysical properties of coumarin-7 dye.

Photophysical investigations of coumarin-7 (C7) dye in different solvents using absorption, steady-state fluorescence and time-resolved fluorescence measurements reveal the behavioral changes of the dye in nonpolar and other solvents. In moderate to higher polarity solvents, the experimental parameters such as fluorescence quantum yield (Phif), fluorescence lifetime (tauf), radiative rate constant (k(f)), nonradiative rate constant (k(nr)) and Stokes' shift (Deltav) follow almost linear correlations with the Lippert-Mataga solvent polarity parameter Deltaf but show unusual deviations in nonpolar solvents. From the observed results, it is inferred that the dye exists in a planar intramolecular charge transfer structure in moderate to higher polarity solvents, but in nonpolar solvents, the dye exists in a nonplanar structure with its 7-NEt2 group adopting a pyramidal type of configuration. Unlike some of the other coumarin dyes, namely coumarin-120 (C120) (4-CH3-7-NH2-1,2-benzopyrone) and coumarin-151 (C151) 4-CF3-7-NH2-1,2-benzopyrone), which also show similar structural changes in nonpolar and other solvents, the C7 dye does not show any activation-controlled deexcitation process in nonpolar solvents. This is attributed to the very slow flip-flop motion of the 7-NEt2 group of the C7 dye in comparison with the very fast flip-flop motion of the 7-NH2 group in the C120 and C151 dyes. Qualitative potential energy diagrams are presented to rationalize the observed results of C7 dye and to compare these with those of the other dyes such as C120 and C151. A support for the observed results and interpretation has also been obtained from quantum chemical calculations on the structures of the C7 dye.

Absorption↗

PubMedDate not supplied

Psoralen and coumarin photochemistry in HSA complexes and DMPC vesicles.

The photochemistry and photophysics of several psoralens and coumarins have been examined in human serum albumin (HSA) complexes and dimyristoylphosphatidylcholine (DMPC) vesicles. Fluorescence spectroscopy indicates that there are multiple binding sites with polarities that are intermediate between those of acetonitrile and water for the substrates complexed to HSA. In the case of the 6,7-dimethoxycoumarin-HSA complex, laser flash photolysis experiments provide evidence for the formation of radical cation in addition to triplet. Radical cations are not detected for other coumarin-HSA complexes, either due to a lower yield of formation or to rapid reaction of an initial radical cation with adjacent amino acids. Fluorescence spectra for coumarins indicate that they are primarily solubilized in the polar headgroup region in DMPC vesicles. Consistent with this, radical cations generated by photoionization are detected in transient experiments. For dimethoxycoumarins the radical cation is long-lived, indicating rapid exit from the vesicle and decay in the aqueous phase. However, 4,5',8-trimethylpsoralen and 7-ethoxy-4-hexadecylcoumarin radical cations are much shorter-lived, presumably due to rapid decay by electron recombination in the vesicle. The results for both HSA complexes and vesicles indicate that radical ions may play a role in psoralen and coumarin photochemistry in a cellular environment.

Binding Sites↗

PubMed1996

Interspecies differences in coumarin metabolism in liver microsomes examined by capillary electrophoresis.

1. A simple, rapid method was developed for studying xenobiotic metabolism by cytochrome P450 in liver microsome preparations. Capillary electrophoresis was used to separate the metabolite from the metabolic mixture. 2. Coumarin is metabolized to 7-hydroxycoumarin by a cytochrome P450 isoenzyme. Human, bovine, gerbil, mouse (Schofield, CO1), rat, rabbit, porcine, and cynomologus monkey microsomal preparations were investigated for coumarin metabolism by determining the content of 7-hydroxycoumarin present after metabolism. 3. Separation of 7-hydroxycoumarin from the reaction mixture was carried out in 50 mM phosphate buffer, pH 6.8, on a fused silica capillary at 25 degrees C and 15 kV. The metabolic matrix consisted of an NADPH regeneration system, 205.5 mu M coumarin, and the microsomal preparation. Standard curves were prepared in the microsomal preparation and the limit of quantification was 6.17 mu M, with a linear range from 0 to 308.5 mu M. 4. The reaction was initiated by the addition of the microsomes. An aliquot of the reaction mixture was removed at specific timed intervals over 2 h and injected directly onto a capillary electrophoresis column and the concentration of 7-hydroxycoumarin determined. The metabolism of coumarin to 7-hydroxycoumarin is greatest in human and monkey microsomes.

Animals↗

PubMed1992

Peroxyl radical scavenging by a series of coumarins.

Sixteen plant-derived or synthetic coumarins with various hydroxyl and other substitutions were tested for their ability to scavenge alkylperoxyl radicals generated in the aqueous phase by the controlled thermolysis of 2,2'-azo-bis-(2-amidinopropane) dihydrochloride (ABAP). Protection by coumarins against inactivation of lysozyme by the radicals was assayed by measuring the loss of turbidity of suspensions of M. lysodeikticus. Ten of the coumarins were potent scavengers of aqueous peroxyl radicals with activities comparable to n-propyl gallate, desferrioxamine, ferrioxamine and trolox c, yielding IC50 values in the range 21 to 92 micromolar. The presence of 6,7-ortho-dihydroxy functions gave compounds of the greatest potency. Scavenging activity was unrelated to ability to chelate iron ions. The active coumarins are attractive candidates for evaluation as protective agents against disorders in which oxidative stress is implicated.

Amidines↗

PubMed2003

Safety aspects of a coumarin-troxerutin combination regarding liver function in a double-blind placebo-controlled study.

OBJECTIVE: Coumarin is reported to elevate liver function tests (LFT) values. In a prospective, placebo-controlled, clinical trial, efficacy and safety of a coumarin-containing combination (SB-LOT) were evaluated in the treatment of chronic venous insufficiency. Here, we report on the drug safety of coumarin with special respect to liver reaction. METHODS: 114 patients were treated with SB-LOT (30 mg coumarin and 180 mg troxerutin t.i.d.) and 117 with placebo during a period of 16 weeks. LFT values (ALT, AST, AP and gamma-GT) were monitored at baseline, 4, 6, 8, 12 and 16 weeks of therapy. Adverse drug reactions were assessed regarding causality. Additionally, lymphocyte proliferation test was used to identify allergic reactions. Logistic regression analysis was performed to identify possible risk factors. RESULTS: No serious adverse drug reactions occurred. Elevations of LFT were assessed as biochemical abnormality. Specific clinical symptoms such as jaundice did not occur. Only 1 patient reported fatigue and exhaustion. Logistic regression estimated a basic risk for elevation of LFT of 4.9% under SB-LOT and 2.1% under placebo. Hepatitis in the history and diseases of the liver were identified as risk factors. CONCLUSION: This evaluation contributes to safety data of SB-LOT in man. LFT elevation is transient and the low risk of the SB-LOT therapy to increase LFT value can be limited when risk factors are considered.

Aged↗

PubMed1999

Novel sensitive high-performance liquid chromatographic method for assay of coumarin 7-hydroxylation.

In this paper, a novel HPLC-based method with fluorometric detection of coumarin 7-hydroxylase is presented. The described method provides a time-effective, more sensitive and specific alternative to the previously used spectrofluorometric assay. Using the developed method, metabolism of coumarin in 11 samples of human liver microsomes was evaluated and 1790+/-690 pmol/min/nmol cytochrome P450 (CYP) activity was found. Kinetic parameters and linearity of coumarin 7-hydroxylation were studied in a reconstituted system consisting of recombinant CYP2A6 expressed in Escherichia coli, rat NADPH-CYP reductase and usual components. It was found that a 3.5 to 30 min time of incubation is suitable for estimation of coumarin 7-hydroxylase activity. Observed Km and Vmax values in the CYP2A6 reconstituted system were 1.48+/-0.37 microM and 3360+/-180 pmol product/min/nmol CYP, respectively.

Animals↗

PubMed1999

[Drug interactions in coumarin anticoagulation].

The clinically most important negative properties of coumarin anticoagulants are their numerous interactions with other drugs. Data in the literature on these interactions are frequently controversial. The causes of this phenomenon are a) the complicated path from ingestion of anticoagulants to their clinical effect and laboratory results, b) interindividual differences in enzyme activity participating in vitamin K metabolism, in the synthesis of hemocoagulation factors and in the biotransformation of coumarin derivatives, c) the different clinical state of the patient on the one hand and the healthy volunteer on the other, d) differences in the biotransformation of different coumarin derivatives and their optic isomers. In the submitted paper the authors describe pharmacokinetic and pharmacodynamic mechanisms of drug interactions of coumarin anticoagulants and their importance for clinical practice. In the conclusion recommendations are submitted to reduce the risk of these interactions.

Anticoagulants↗

PubMed2001

Consumption of watercress fails to alter coumarin metabolism in humans.

Watercress is an excellent source of phenethyl isothiocyanate (PEITC), an effective inhibitor of nitrosamine carcinogenesis in rodents. The mechanism of inhibition is believed to be due in part to inhibition of cytochrome P450 (P450) enzymes. P450 2A6 is a catalyst for the metabolic activation of several nitrosamines. In this study, we investigated the effect of watercress consumption on coumarin 7-hydroxylation, a P450 2A6-specific reaction, in a group of 15 nonsmoking, healthy volunteers. The urinary excretion of 7-hydroxycoumarin (7OHC) was determined. For 6 of the 15 subjects, watercress consumption decreased the amount of 7OHC excreted in the first 2 h following coumarin administration. However, the mean 0- to 2-h excretion of 7OHC for all 15 subjects was not significantly lowered by the consumption of watercress, 2.8 +/- 0.78 versus 3.1 +/- 0.53 mg (+/-S.D.). The mean 7OHC excreted from 2 to 4 h (1.1 +/- 0.50 mg) was significantly higher (P = 0.027) during watercress consumption than before (0.77 +/- 0.22 mg), suggesting a delay in coumarin metabolism. Total excretion of 7OHC was unaffected by watercress consumption. Therefore, under the conditions of our study, PEITC and other constituents of watercress had at most a marginal inhibitory effect on P450 2A6-catalyzed coumarin 7-hydroxylation.

Adult↗

PubMed1975

[Effect of various coumarins on the intestinal absorption of galactose in vivo (author's transl)].

The effect of various coumarins on the active transport of galactose by small intestine in chick and rat was studied, using the in vivo technique of sucessive absorptions. A 10(-4) M concentration of the different coumarins inhibits the absorption of galactose in the chick. This effect persists in successive absorptions without coumarin. In rat, inhibition of galactose active transport by coumarins was observed at 10(-3) M concentration.

Animals↗

PubMed2004

[Extraction of coumarins from Angelica dahurica by supercritical extraction and GC-MS analysis].

OBJECTIVE: To extract coumarins from Angelica Dahurica by supercritical CO2. METHOD: Six-factor and three-level orthogonal experimental design was used to optimize the SFE conditions as guided by the content of total coumarins in the extract. Constituents of the coumarins were analyzed by GC-MS, and their relative contents were determined by normalization method of areas. RESULT: Total 15 coumarins were separated, the relative contents of oxyimperatorin, imperatorin and isoimperatorin being up to 42.40%, 22.14% and 12.12% respectively. Optimum extraction process was established: 21 MPa as extraction pressure, 50 degrees C as extraction temperature, 3 h as time for extraction, 20 mesh as pulverized degree, 6.5 MPa as separation pressure and 30 degrees C as separation temperature. CONCLUSION: Changes in extraction pressure, temperature, time, pulverized degree and separation pressure affect the extracting results remarkably.

Angelica↗

PubMedDate not supplied

Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity.

A preliminary exploration of coumarin derivatives as novel multidrug resistance (MDR) modulators was carried out to determine the basic features of the structure responsible for the MDR reversal activity. Among 44 coumarins, 14 compounds moderately induced the reversal of MDR (fluorescence activity ratio (FAR) values > 1). The most active compound, 6-hydroxy-3-(2-hydroxyethyl)-4-methyl- 7-methoxycoumarin [C34], was equally potent as a MDR modulator verapamil. These data show a relationship between the chemical structure and MDR-reversal effect on tumor cells. All coumarins tested were more cytotoxic against tumor cells than normal cells. Several compounds displayed potent cytotoxic activities (CC50 15 - 29 microg/mL in HSC cells), comparable with that of gallic acid (CC50 = 24 microg/mL). Both 6-hydroxy- 7-methoxy-4-methyl-3-isopropylcoumarin [C43] and 3-ethyl-6-hydroxy- 7-methoxy-4-methylcoumarin [C44] showed the highest tumor-specific cytotoxicity (SI value = 4.1 and 3.6, respectively). We conclude that coumarins are potentially potent new MDR modulators with low toxicity against normal cells. A deeper understanding of the relationship between their structures and their potency will contribute to the design of optimal agents.

Cell Line, Tumor↗

PubMed2005

Antibacterial activity of 1-methyl-7-methoxy-beta-carboline and its phenacyl and coumarine analogues.

Antibacterial activity of 1-methyl-7-methoxy-beta-carboline (harmaline) and its phenacyl and coumarine analogues 1-(3-nitro-phenyl)-(2-(7-methoxy-1-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-ethanone (II), 1-(3,4-dihydroxy-phenyl)-2-(7-methoxy-1-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-ethanone (III) 7-(methoxy-beta-carboline),15-24,de-hydro(19,20-dimethoxy)coumarine (IV), 7-(methoxy-beta-carboline)15-24,dehydro(20-methoxy)coumarine (V) were studied by disc diffusion method. All compounds were tested against three gram positive and four gram-negative bacteria. Parent compound showed good activity. All compounds revealed better results against gram positive as compared to gram-negative bacteria. 1-(3,4-Dihydroxy-phenyl)-2-(7-methoxy-1-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-ethanone (III) was found most potent compound showing broad spectrum activity when compared with all synthesized analogues. Coumarine analogues showed more or less same activity indicating that number and position of methoxy groups are not important regarding antimicrobial activity.

Anti-Bacterial Agents↗

PubMed1991

Combined coumarin and omental transfer treatments for canine proximal obstructive lymphoedema.

In a canine model both coumarin treatment (believed to act by increased local proteolysis) and surgical transfer of a bridge of vascularized, lymphatic-rich omentum cause significant reduction of experimental lymphoedema. The present paper describes the effects of consecutive application of these two types of treatment. Ten dogs were divided into two equal groups: Group 1 Coumarin treatment, 6 months; no treatment, 6 months; omental transfer, 6 months; or Group 2 Omental transfer, 12 months (biopsied at 6 months); coumarin treatment, 6 months. Prior to treatment the excess limb circumferences were 2.66 and 3.01 cm in Groups 1 and 2 respectively. In Group 1, 6 months coumarin treatment alone reduced swelling by 0.78 cm and the final reduction in swelling at 18 months was 1.03 cm. In Group 2, reduction in swelling 6 months after omental transfer alone was 0.96 cm and the final reduction at 18 months was 2.05 cm. The findings indicate that in Group 1 there is an additive effect of the two types of treatment. However, in Group 2 it is not possible to be certain whether the improvement that occurred between 6 and 18 months also reflects an additive effect or a later consequence of the earlier omental transfer.

Animals↗

PubMed1990

[Mechanism of the antiasthmatic effect of total coumarins in the fruit of Cnidium monnieri (L.)Cuss].

Total coumarins in the fruit of Cnidium monnieri show a marked protective effect against bronchial asthma induced by inhalation of histamine in conscious guinea pig. In vitro these total coumarins can relax the contraction of the isolated trachea in guinea pigs induced by histamine as well as increase the perfusion rate of isolated lung preparation of guinea pig. These actions, however, may be blocked by propranolol. Besides, these coumarins cannot increase the heart rate and arterial blood pressure in anesthetized rats. All this shows that the antiasthmatic effect of total coumarins in the fruit of Cnidium monnieri is mediated by beta 2-receptor.

Animals↗

PubMed1987

[Teratogenic effect of coumarins].

Coumarins administered in early pregnancy can cause malformations. This so-called coumarin embryopathy is characterized by malformations such as those occurring in chondrodysplasia punctata of the Conradi-Hünermann type, i.e. a syndrome which has been known since 1914. A case observed after coumarin administration (Falithrom) in early pregnancy is described with the features considered typical: Hypoplasia of the nasal bridge and stippled calcification of the skeleton, in particular stippled epiphyses of the long bones. According to reports in the literature, the risk of fetal abnormality amounts to some 30 per cent. This entails in practice the requirement for absolute contraindication for coumarins in early pregnancy (first trimester). Finally, possibilities of an acceptable anticoagulant therapy during pregnancy are discussed.

Abnormalities, Drug-Induced↗

PubMed1985

Inhibition of the formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid from arachidonic acid in polymorphonuclear leukocytes by various coumarins.

The effects of various coumarins (i.e. esculetin, daphnetin and fraxetin) on the formation of the 5-lipoxygenase product, 5-HETE, and the cyclooxygenase product, HHT, were studied. Esculetin (6,7-dihydroxycoumarin) was found to inhibit the formation of 5-HETE more strongly than HHT; its concentrations for 50% inhibition (IC50) were 1.46 +/- 1.02 microM for the formation 5-HETE and 57.3 +/- 17.3 microM for the formation of HHT. Daphnetin (7,8-dihydroxycoumarin) and fraxetin (6-methoxy-7,8-dihydroxycoumarin) also inhibited the formation of the 5-lipoxygenase product, 5-HETE, and the cyclooxygenase product, HHT; their IC50 values were, respectively, 6.90 +/- 2.07 microM and 2.57 +/- 0.088 microM for the formation of 5-HETE and 139.0 +/- 30.0 microM and 532.5 +/- 33.0 microM for the formation of HHT. The monohydroxy coumarin derivatives umbelliferone (7-hydroxycoumarin) and scopoletin (6-methoxy-7-hydroxycoumarin) and the coumarin glucosides fraxin (6-methoxy-7,8-dihydroxycoumarin 8-O-D-glucoside) and esculin (6,7-dihydroxycoumarin 6-O-D-glucoside) also inhibited the formation of 5-HETE, though less strongly. 4-Hydroxycoumarin and coumarin had no effect on either 5-lipoxygenase or cyclooxygenase at concentrations of up to 1 mM. Esculetin inhibited the formation of 5-HETE noncompetitively. In contrast, the dimethoxycoumarin fraxidin (6,8-dimethoxy-7-hydroxycoumarin) inhibited the formation of HHT more strongly than the formation of 5-HETE at a concentration of 1 mM.

Animals↗