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At least 19 recordsLinked to original sources
PubMed1989

Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes: comparison with dihydrocoumarin and other coumarin metabolites.

Single doses of coumarin (125 mg/kg, ip) produced a depletion of hepatic nonprotein sulfhydryl groups (mainly reduced glutathione; GSH) in young male Sprague-Dawley rats after 2 hr and increased liver weight and produced hepatic centrilobular necrosis after 24 hr. Coumarin also produced time- and dose-dependent toxic effects in primary rat hepatocyte cultures. A marked reduction of GSH levels was also observed in vitro and this was not due either to the formation of oxidized glutathione (GSSG) or to the leakage of GSH and/or GSSG from the hepatocytes. Coumarin-induced toxicity in rat hepatocytes could be inhibited by the cytochrome P450 inhibitors ellipticine and metyrapone and potentiated by depleting hepatocyte GSH levels with diethyl maleate. In contrast to coumarin, dihydrocoumarin--which lacks the 3,4-double bond--produced little toxicity in rat hepatocytes either in vivo (127 and 254 mg/kg, ip) or in vitro. Similarly, coumarin was more toxic to rat hepatocytes than a number of known coumarin metabolites including 3- and 7-hydroxycoumarin and o-hydroxyphenylacetic acid. The results of these studies demonstrate a good in vivo/in vitro correlation for the effects of coumarin and dihydrocoumarin in rat hepatocytes. Furthermore, the data suggest that coumarin hepatoxicity in the rat is due to coumarin bioactivation by cytochrome P450-dependent enzymes to a toxic metabolite(s), which may be a coumarin 3,4-epoxide intermediate. GSH appears to protect against coumarin-induced toxicity possibly by the formation of conjugates with the toxic coumarin metabolite(s).

Animals↗
PubMed1994

Studies on the acute effects of coumarin and some coumarin derivatives in the rat.

The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives. Male Sprague-Dawley rats were given single ip doses of corn oil (control), coumarin (0.86 and 1.71 mmol/kg body weight), 3,4-dimethylcoumarin (3,4-DMC, 1.71 and 2.57 mmol/kg), 3-, 4- and 6-methylcoumarins (3-MC, 4-MC and 6-MC, 1.71 mmol/kg) and 3- and 4-methyloctahydrocoumarins (3-MOHC and 4-MOHC, 2.57 mmol/kg) and hepatotoxicity assessed after 24 hr. Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, none of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Treatment with coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin O-deethylase activities, whereas one or both mixed-function oxidases appeared to be induced by treatment with 3,4-DMC, 4-MC, 3-MOHC and 4-MOHC. These results provide further evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. That 3- and/or 4-methyl substitution (i.e. 3-MC, 4-MC and 3,4-DMC) leads to a reduction in coumarin-induced hepatotoxicity, due to diminished formation of 3,4-epoxide intermediates, was confirmed by the results of molecular orbital calculations.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1981

Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form.

Prolonged-release tablets containing coumarin were compared to intravenous and peroral administration of coumarin solution in man. Unchanged coumarin, the Phase 1 metabolite 7-hydroxycoumarin, and the Phase II metabolite 7-hydroxycoumarin glucuronide were determined in whole blood. Upon peroral administration, only approximately 1 per cent coumarin was found unchanged in the systemic circulation. However, the amount of the glucuronide found indicates complete absorption with extensive first-pass effect. When the prolonged-release dosage form was compared to the peroral solution, the extent of bioavailability of coumarin was 35 per cent, whereas the 7-hydroxycoumarin glucuronide was totally available. This supports the hypothesis that coumarin might be a prodrug and 7-hydroxycoumarin the active moiety. The drug liberation of coumarin from the sustained-release tablets follows first-order kinetics. A linear correlation was found between per-cent of drug released in vitro and the area under the concentration-time curve, AUC (O-t), of total 7-hydroxycoumarin (7HC + 7HCG).

Biological Availability↗
PubMed1977

Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man.

The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.

Administration, Oral↗
PubMed1998

A comparison of artificially-depleted, lyophilized coumarin and fresh coumarin plasmas in thromboplastin calibration. European Concerted Action on Anticoagulation.

Artificially-depleted lyophilized plasmas and lyophilized coumarin plasmas were prepared and compared with fresh coumarin plasmas to assess their comparative reliability in local thromboplastin calibration using the manual prothrombin time (PT) technique. Their certified PT values were inserted in turn on the vertical axis in place of the PT obtained with fresh coumarin plasmas. PT results were obtained at eight ECAA national laboratories ('test centres') and inserted on the horizontal axis. The resulting thromboplastin calibration slopes were compared with conventional fresh coumarin plasma calibration slopes at the same 'test centres'. When 60 artificially-depleted plasmas were substituted for 60 fresh plasmas, the mean calibration slopes with the human plain International Reference Preparation (IRP) were 4.2% higher. For comparison with 20 lyophilized coumarins, three sets of 20 artificially-depleted plasmas were selected in sequential order from the 60. The lyophilized coumarin plasmas gave a mean deviation of 9.6% from the fresh plasma calibration slopes compared with values of 2.0%, 6.1% and 11.7% for the three sets of 20 depleted plasmas. Although both types of lyophilized plasma calibration slopes give measurable differences from conventional fresh plasmas, these may be regarded as acceptable in clinical terms.

Blood Coagulation Tests↗
PubMed2004

Studies on coumarins and coumarin-related compounds to determine their therapeutic role in the treatment of cancer.

The Benzopyrones are a group of compounds whose members include coumarins and flavonoids. Dietary exposure to benzopyrones is quite significant, as these compounds are found in vegetables, fruit, seeds, nuts, coffee, tea and wine. It is estimated that the average western diet contains approximately 1 g/day of mixed benzopyrones. It is, therefore, not difficult to see why extensive research into their pharmacological and therapeutic properties is underway over many years. Coumarin is a natural substance that has shown anti-tumour activity in vivo, with the effect believed to be due to its metabolites (e.g. 7-hydroxycoumarin). This review is based on recent studies of coumarins and coumarin related compounds. Therefore, the focus will be on these relevant compounds and their therapeutic importance. A recent study has shown that 7-hydroxycoumarin inhibits the release of Cyclin D1, which is overexpressed in many types of cancer. This knowledge may lead to its use in cancer therapy. Esculetin inhibits growth and cell cycle progression by inducing arrest of the G(1) phase in HL-60 leukaemia cells, resulting from the inhibition of retinoblastoma protein phosphorylation. Recent studies investigating the potential of flavonoids as therapeutic agents have suggested they may have use in various therapeutic settings ranging from leukaemia treatment to the treatment of patients with HIV. Genistein is a well-known isoflavone and is a tyrosine kinase inhibitor. Studies have indicated that genistein elicits inhibitory effects on cell growth of various carcinoma cell-lines and may be a potential candidate for cancer therapy. In our research, we have investigated the effects of coumarins and coumarin-related compounds on a panel of cell-lines. The most recent work involves two cell-lines, MCF-7 a breast carcinoma and A549 a lung carcinoma. Microtitre assays were performed along with real-time analysis of cell viability using a biosensor called the Cytosensor microphysiometer. These studies suggest that both genistein and esculetin exerted the most potent inhibitory effect on cell growth in comparison to the other two compounds.

Animals↗
PubMed1998

Antitumor-activities of coumarin, 7-hydroxy-coumarin and its glucuronide in several human tumor cell lines.

Coumarin is found in many medicinal plants and therefore also used in phytomedicine for the treatment of venous diseases. The metabolic pathways of coumarin in the human body lead to the intermediate 7-hydroxy-coumarin and consequent glucuronidation in the intestine and liver. The antitumor activities of coumarin (C) and its known metabolite 7-hydroxy-coumarin (7-OH-C) were tested in several human tumor cell lines. C as well as 7-OH-C inhibited cell proliferation of a gastric carcinoma cell line, a colon-carcinoma cell line (Caco-2), a hepatoma-derived cell line (HepG2) and a lymphoblastic cell line (CCRF CEM) in a concentration-dependent way, the IC50-values were 1.59-3.57 mM for C and 0.68-2.69 mM for 7-OH-C. The glucuronide of 7-OH-C was ineffective in this respect.

Antineoplastic Agents↗
PubMedDate not supplied

Coumarin mercapturic acid isolated from rat urine indicates metabolic formation of coumarin 3,4-epoxide.

A coumarin mercapturic acid, N-acetyl-S-(3-coumarinyl)cysteine, has been identified in the urine of coumarin-treated rats. [14C]Coumarin was applied by gavage as a single dose to male Wistar rats (10-150 mg/kg body weight). Twenty-four-hour urine was collected, and the deproteinized concentrate was analyzed for radiolabeled metabolites by HPLC. The new mercapturic acid metabolite is supposed to result from oxidative biotransformation of coumarin to its 3,4-epoxide and subsequent coupling with glutathione.

Acetylcysteine↗
PubMed1994

Structures of new coumarins and antitumor-promoting activity of coumarins from Angelica edulis.

From the fruits of Angelica edulis Miyabe (Umbelliferae), three new angular furanocoumarins, edulisin III (1), edulisin IV (2), and edulisin V (3), were isolated along with three known coumarins, 2'(S), 3'(R)-3'-isobutyryloxy-4'-acetoxy-2',3'-dihydrooroselol (4), edultin (5), and 2'(S),3'(R)-3'-senecioyloxy-4'-acetoxy-2',3'-dihydrooroselol (6), respectively. The structures of 1 and 2 were established to be 2'(S),3'(R)-3'-(2-methylbutyryloxy)-4'-acetoxy-2',3'-dihydrooro selol and 2'-(S),3'(R)-3'-propyryloxy-4'-acetoxy-2',3'-dihydrooroselol by chemical studies and spectral analyses. Coumarin 3 was proved to be 3'-(2-methylbutyryl-oxy)-4'-angeloyloxy-2',3'-dihydrooroselol++ + by chemical and spectral analyses and H-C COLOC. Coumarins 1-6 were examined for the effects on tumor-promotor induced phenomena in vitro. Among these coumarins, 3 showed the most potent inhibitory activity on 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated 32Pi incorporation into phospholipids of cultured cells.

Antineoplastic Agents, Phytogenic↗
PubMed1983

Pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in the blood and brain of gerbils following intraperitoneal administration of coumarin.

Blood and brain concentration-time profiles were obtained in gerbils following intraperitoneal administration of coumarin (C). The data were fit to one- or two-compartment models using several computer programs including NONLIN, modified ESTRIP, RESID and AUC-RPP. The data indicate that coumarin distributes rapidly into the brain tissue reaching about one half the blood concentration at peak time. The peak time brain coumarin concentration and subsequent rapid removal from brain correlates well with the transient sedative effect of coumarin. Area under the curve estimations indicate that 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide distribute into brain tissue to a negligible extent if at all. The pharmacokinetic profile of C as well as the metabolic 7-hydroxylation and glucuronidation found in the blood of the gerbil is similar to that found in man. This would suggest that the gerbil is potentially a good model for pharmacokinetic and pharmacological investigations of C for correlation with human studies.

Animals↗
PubMed2002

Deactivation behavior and excited-state properties of (coumarin-4-yl)methyl derivatives. 2. Photocleavage of selected (coumarin-4-yl)methyl-caged adenosine cyclic 3',5'-monophosphates with fluorescence enhancement.

A series of axial and equatorial diastereomers of (coumarin-4-yl)methyl-caged adenosine cyclic 3',5'-monophosphates (cAMPs), 1-6, having methoxy, dialkylamino, or no substituent in the 6- and/or 7-positions, and their corresponding 4-(hydroxymethyl)coumarin photoproducts 7-12 have been synthesized. The photochemical and UV/vis spectroscopical properties (absorption and fluorescence) of 1-6 and 7-12 have been examined in methanol/aqueous HEPES buffer solution. Donor substitution in the 6-position causes a strong bathochromic shift of the long-wavelength absorption band, whereas substitution in the 7-position leads only to a weak red shift. The photochemical cleavage of the caged cAMPs was investigated, and the photoproducts were analyzed. Photochemical quantum yields, fluorescence quantum yields, and lifetimes of the excited singlet states were determined. The highest values of photochemical quantum yields (photo-S(N)1 mechanism) were obtained with caged cAMPs having a donor substituent in the 7-position of the coumarin moiety, caused by electronic stabilization of the intermediately formed coumarinylmethyl cation. With donor substitution in the 6-position, the resulting moderate electronic stabilization of the coumarinylmethyl cation is overcompensated by the strong bathochromic shift, reducing the energy gap between the excited-state S(1) and the corresponding coumarinylmethyl cation. The rate constant for the ester cleavage and liberation of cAMP is about 10(9) s(-1), estimated for the axial isomer of 6 by analysis of the fluorescence increase of the alcohol 12 formed upon laser pulse photolysis.

Coumarins↗
PubMed2003

Chemical constituents of Calophyllum brasiliense. 2. Structure of three new coumarins and cancer chemopreventive activity of 4-substituted coumarins.

Continuing our search for cancer chemopreventive agents from natural sources, we examined constituents of the stem bark of Calophyllum brasiliense. Three new 4-substituted coumarins named brasimarins A (2), B (3), and C (4) were isolated and characterized, along with 11 known coumarins belonging to the calanolides or inophyllums. We also discuss the inhibitory effects of these coumarins on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.

Anticarcinogenic Agents↗
PubMed1975

Effect of coumarin and some coumarin derivatives on active transport and passive diffusion of sugars by chicken and rat intestine, in vitro.

The effect of coumarin, 4-hydroxycoumarin, coumarin-3-carboxylic acid and acenocoumarol on the active transport of D-galactose and the passive diffusion of arabinose by intestinal sacs was studied. All these substances, when added to the mucosal medium of incubation at concentrations from 10(-4) to 10(-3) M, inhibit the active transport of D-galactose and increase the diffusion of arabinose. Oxygen uptake by the intestinal tissue is only inhibited by coumarin-3-carboxylic acid. The results suggest that the effects obtained are probably due to an alteration in intestinal permeability, to inhibition of cell metabolism and to molecular size.

Acenocoumarol↗
PubMed1978

Histological and histochemical investigations of the epiphyseal cartilage in rats after administration of heparin, coumarin as well as coumarin and diphosphonate (EHDP).

Heparin and coumarin (Marcumar) as well as coumarin combined with a diphosphonate (EHDP) were examined histologically and histochemically with regard to their effect on the structure of the epiphyseal cartilage in rats. Topo-optical reactions were used to assess the submicroscopic structural changes in the developing trabeculae of metaphysis. The zone of resting cartilage and the zone of young proliferation cartilage in epiphyseal plates revealed a reduced cell count due to the influence of anticoagulants. With regard to the matrix of the epiphyseal plate, it may be stated that its ultrastructure appeared partly regular and that, on the other hand, large areas of degeneration were detected in the connective-tissue. The negative effect of anticoagulants on the ground substance could not be reduced definitely by means of a diphosphonate (EHDP) in conjunction with Marcumar which was administered simultaneously.

Animals↗