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PubMed2002

Variation in coumarin 7-hydroxylase activity associated with genetic polymorphism of cytochrome P450 2A6 and the body status of iron stores in adult Thai males and females.

The relationships between catalytic activity of cytochrome P450 2A6 (CYP2A6), polymorphism of CYP2A6 gene, gender and levels of body iron stores were analysed in a sample group of 202 apparently healthy Thais, aged 19-47 years. Eleven individuals were found to have high activity of CYP2A6, judged by the relatively large amounts (11.2-14.6 mg) of 7-hydroyxcoumarin (7-OHC) excreted 3 h following administration of 15 mg of coumarin. Ten individuals, however, did not excrete any 7-OHC. Of these 10, four were found to have no CYP2A6 gene (whole gene deletion; CYP2A6*4 allele). The frequency of the CYP2A6 alleles; *1A, *1B and *4 in the whole sample group was 52, 40 and 8% while the frequency of the CYP2A6 gene types; *1A/*1A, *1A/*1B, *1B/*1B, *1A/*4, *1B/*4, *4/*4 was 29, 41, 16, 7, 5 and 2%. Subjects having CYP2A6*1A/*1B gene-type group were found to have higher rates of coumarin 7-hydroxylation compared with those of the CYP2A6*1B/*1B and CYP2A6*1A/*4 gene types. The inter-individual variability in CYP2A6 catalytic activity was therefore attributed in part to the CYP2A6 genetic polymorphism. Variation in CYP2A6 activity in this sample group was not associated with gender but, interestingly, it did show an inverse association with plasma ferritin; an indicator of body iron stores. Higher rates of coumarin 7-hydroxylation were found in individuals with low body iron stores (plasma ferritin < 20 microg/l) compared with subjects having normal body iron store status. Subjects (n = 16) with iron overload (plasma ferritin > 300 microg/l) also tended to have elevated rates of coumarin 7-hydroxylation. These results suggest an increased CYP2A6 expression in subjects who have excessive body iron stores. Further investigations into the underlying factors that may lead to increased expression of CYP2A6 in association with abnormal body iron stores are currently in progress in our laboratory.

Adult↗

PubMed1992

Human and mouse liver coumarin 7-hydroxylases do not metabolize warfarin in vitro.

1. The contribution of human P450 2A6 and mouse P450 2a-5 isoenzymes, both highly active in coumarin 7-hydroxylation, to the metabolism of warfarin was studied in several in vitro systems with human and mouse liver preparations. 2. The reconstituted P450 2a-5 purified from DBA/2 mouse liver did not metabolize warfarin. 3. An anti-P450 2a-5 antibody did not consistently inhibit any of the warfarin biotransformation reactions catalyzed by human or mouse liver microsomes, although coumarin 7-hydroxylation was inhibited by over 90%. 4. In some human microsomal samples, 4- and 8-hydroxylations of warfarin were inhibited to some extent by the anti-P450 2a-5 antibody. 5. Warfarin (less than 1 mM) did not inhibit coumarin 7-hydroxylation by human or mouse liver microsomes in vitro. 6. We conclude that mouse and human coumarin 7-hydroxylases do not oxidise warfarin.

Adult↗

PubMed2004

Coumarin necrosis induced by renal insufficiency.

Cutaneous necrosis is an infrequent complication of coumarin therapy. Skin necrosis has usually been reported in patients with congenital protein C deficiency or, less commonly, protein S deficiency. However, this complication may also occur with acquired and transient protein C and/or S deficiency. In coumarin therapy there is a relatively hypercoagulable state at the start of treatment, and most lesions appear between the third and sixth days. We describe a 75-year-old man receiving coumarin therapy (acenocumarol) for 7 years who was given a nonsteroidal anti-inflammatory agent (diclofenac) for a pain in his knee. Two days later, his renal function deteriorated and skin necrosis became evident. Biopsy showed histological changes consistent with coumarin-induced necrosis. Protein C and S levels were normal. We concluded that in our patient acute renal insufficiency aggravated by diclofenac treatment probably associated with an inadvertent withdrawal could have been the precipitating factor for transient protein C deficiency.

Acenocoumarol↗

PubMed1984

Purification and characterization of a microsomal cytochrome P-450 with high activity of coumarin 7-hydroxylase from mouse liver.

Phenobarbital-induced coumarin 7-hydroxylase is high in DBA/2J and low in C57BL/6N inbred mice; this genetic difference is encoded by the Coh locus on chromosome 7. The aim of this study was to develop an antibody specific for this cytochrome P-450 polymorphism. P-450 fractions, highly specific for phenobarbital-inducible coumarin 7-hydroxylase activity, were purified from DBA/2J and C57BL/6N mouse liver microsomes. Both proteins are 49 kDa, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Soret peaks of the reduced cytochrome . CO complexes are 451 nm. Reconstituted DBA/2J coumarin 7-hydroxylase activity exhibits a V twice as high as, and a Km value 10-fold less than, the reconstituted C57BL/6N activity. Antibodies were raised in rabbit. By Ouchterlony immunodiffusion, both antibodies show 100% cross-reactivity with DBA/2J and C57BL/6N microsomes and purified antigens. Yet, DBA/2J but not C57BL/6N 7-hydroxylase activity is inhibited by the antibody to DBA/2J P-450. Both DBA/2J and C57BL/6N activities are blocked by the antibody to C57BL/6N P-450. Neither antibody has any effect on liver microsomal d-benzphetamine N-demethylase, ethylmorphine N-demethylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase, acetanilide 4-hydroxylase, or aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity. The DBA/2J protein most specific for phenobarbital-induced coumarin 7-hydroxylation is designated 'P-450Coh'. Anti-(P-450Coh) precipitates a relatively minor 49-kDa protein from detergent-solubilized microsomes and from in vitro translation of poly(A+)-enriched total RNA of phenobarbital-treated DBA/2J mouse liver, whereas the major phenobarbital-induced P-450 proteins exhibit a molecular mass of about 51 kDa. The immunoprecipitated translation products correspond to a messenger RNA of 2100 +/- 100 nucleotides.

Animals↗

PubMed1993

[Management of chronic venous insufficiency with the combination of coumarin (Syncoumar) and oral pentosan polysulfate (PPS, SP 54) (preliminary report)].

Fibrinolysis of 19 patients who developed CVI after deep vein thrombosis was examined. Mean age of patients at the first thrombosis was 31.8 years. For testing fibrinolysis fibrinogen, plasminogen, AP, ECLT, with venous occlusion were determined. In 10 patients t-PA and PAI-1 activities were also measured and plethysmography was carried out. For screening blood coagulation abnormalities of TCT count, PT, APTT, TT, AT III, protein C were tested. The common abnormality was the decreased fibrinolysis. Patients had been on coumarin for 6.14 years before entering the study. Under coumarin treatment 6 patients had relapsed DVT, 4 had crural ulcer and CVI deteriorated in 8 patients. Therefore we added fibrinolysis increasing PPS to coumarin. PPS dose was individually determined by PPS loading test (150-500 mg). Mean observation time with the combined treatment was 2.92 years. Clinical check up and fibrinolysis test were carried out every 6 months. Clinical improvement occurred in 13 patients, (decrease of swelling, pain etc). Two out of 4 patients with stasis ulcer experienced complete healing; in 1 the ulcer territory diminished in size. Maximum venous outflow improved in 7 patients, 3 patients were non-responders. We observed an increase of fibrinolysis in 10 patients. Venous occlusion enhanced the fibrinolysis increasing effect of PPS. The activity reached its maximum by the first control. The fibrinolysis increase and the clinical improvement do not always run parallel, therefore other effects of PPS as the reason for being beneficial in CVI must be considered (antiinflammatory, ect.). Combination of coumarin and PPS seems to be an effective therapy in CVI with decreased fibrinolysis.

Acenocoumarol↗

PubMed1996

[Liver injury caused by coumarin anticoagulants: experience of the IKS (Intercanton Monitoring Station) and the SANZ (Swiss Center for Drug Monitoring)].

Drug-induced liver diseases are potentially avoidable. Hepatotoxic drugs can mimic virtually any form of liver disease. Among all voluntary adverse drug reaction reports to central registries, 4-7% refer to drug-induced liver diseases. We analyze all cases of coumarin-induced hepatic injuries reported on a voluntary basis to the Swiss Drug Monitoring Centre (SANZ) and the Pharmacovigilance Centre (IKS) from 1981 to 1995. During this period the SANZ collected 9720 reports, 674 of which (6.9%) referred to the liver and the biliary tract. In only 11 reports an oral anticoagulant was involved. In 8 cases we assumed at least a possible causal relationship. 2 more cases were reported directly to the IKS. Among these 10 cases 7 were related to phenprocoumon and 3 to acenocoumarol. In 4 cases elevated concentrations of liver enzymes were measured 2-7 days after the beginning of therapy. In the remaining 6 cases the clinical picture was so severe that the patients had to be hospitalized. These 10 cases are discussed and compared with the cases published in the literature. According to our data, hepatic disorders induced by coumarin-anti-coagulants are rare. If hepatitis is diagnosed in a patient treated with oral anticoagulants, the differential diagnosis of a coumarin-induced hepatic injury has to be considered. Crossreactions between the coumarin derivatives phenprocoumon and acenocoumarol are possible.

Acenocoumarol↗

PubMed1963

COUMARIN THERAPY. PROTHROMBIN ACTIVITY AFTER TERMINATION OF TREATMENT.

Twelve patients receiving coumarin type hypoprothrombinemic agents were studied before, during and after termination of therapy, the prothrombin proconvertin method having been used to assay the prothrombin activity complex. In no instance was post treatment "rebound" demonstrated. Prothrombin activity levels returned to pretreatment values only after ten days following termination of coumarin or Dicumarol administration. If a reactivation of thrombotic tendency occurs following discontinuance of anticoagulant therapy, it would not appear to be related to a "rebound" of prothrombin activity above that which is "normal" for the individual patient. Patients tend to return to the same level of prothrombin activity present before initiation of coumarin therapy.

Anticoagulants↗

PubMed1994

Approach to detect substrates suitable to measure the coumarin 7-hydroxylase (Cyp 2a-5)-structure-activity relationships.

Besides coumarin, which up to now has remained the most selective substrate for the coumarin 7-hydroxylase (Coh), 7-ethoxycoumarin, quinoline, 4-methylcoumarin, 7-ethoxy-4-methylcoumarin, 7-ethoxy-4-ethylcoumarin, and psoralen are suitable for this enzyme. The quantification of the suitability of a substrate to selectively measure the coumarin 7-hydroxylase is achieved by a graphic method. Requirements for serving as a substrate of the Coh are bicyclic ring systems with an electron rich moiety.

Animals↗

PubMed2006

Lipophilicity plays a major role in modulating the inhibition of monoamine oxidase B by 7-substituted coumarins.

A series of coumarin derivatives (1-22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC(50) values in the micromolar to low-nanomolar range. A structure-activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r(2)=0.72) between pIC(50) and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1 h after intraperitoneal administration of high doses (100 and 300 mumol kg(-1)), revealing its ability to cross the blood-brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues.

Animals↗

PubMed2003

[7-(Dialkylamino)coumarin-4-yl]methyl-Caged Compounds as Ultrafast and Effective Long-Wavelength Phototriggers of 8-Bromo-Substituted Cyclic Nucleotides.

[7-(Dimethylamino)coumarin-4-yl]methyl (DMACM) and [7-(diethylamino)coumarin-4-yl]methyl (DEACM) esters of 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) are described as novel caged compounds for 8-bromo-substituted cyclic nucleotides. Synthesis is accomplished by treatment of the free acids of the cyclic nucleotides with the corresponding 7(dialkylamino)-substituted 4(diazomethyl)coumarins. Irradiation of the DMACM- and DEACM-caged cyclic nucleotides with UV light stimulates the release of the cyclic nucleotides within roughly a nanosecond. The new caged compounds are resistant to hydrolysis in aqueous buffers and exhibit long-wavelength absorption properties with maxima at 400 nm, high extinction coefficients, and high quantum yields (0.15-0.31). Their favorable properties render these compounds the most efficient and rapid phototriggers of 8-bromo-substituted cyclic nucleotides known. The usefulness of the compounds for physiological studies under nondamaging light conditions was examined in HEK293 cells expressing the alpha subunit of the cyclic-nucleotide-gated (CNG) channel of cone photoreceptors (CNGA3) and of olfactory neurons (CNGA2) by using confocal laser scanning microscopy and the patch clamp technique.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1976

Determination of coumarin and umbelliferone mixtures in whole blood by spectrophotofluorometry.

A spectrophotofluorometric method is described for the quantitative analysis of coumarin, umbelliferone, and mixtures thereof in whole blood. The two drugs were selectively isolated from blood by solvent extraction. Analysis of the isolated coumarin was based on the measurement of the fluorophore at activation and emission wavelengths of 361 and 491 nm, respectively. The fluorophore was obtained by irradiating an alkaline methanolic solution of the drug with UV light. A linear relationship between fluorescence and concentration existed over the concentration range of 0.02-0.2 mug of coumarin/ml. A mean recovery value of 94.8% was obtained from whole blood. The isolated umbelliferone was determined according to established methods at activation and emission wavelengths of 370 and 450 nm, respectively, and the limit of detection was 10 times more sensitive than previously reported. A linearity response was obtained between 1 and 10 ng of umbelliferone/ml. Good recovery data for mixtures of coumarin and umbelliferone in whole blood were obtained.

Coumarins↗

PubMed2005

Simultaneous separation and purification of five bioactive coumarins from the Chinese medicinal plant Cnidium monnieri by high-speed counter-current chromatography.

Cnidium monnieri (L.) Cusson is a well-known Chinese medicinal plant, which has been used for the treatment of impotence, frigidity, and skin-related diseases, and exhibits strong antipruritic, antiallergic, antidermatophytic, antibacterial, antifungal, and antiosteoporotic activities. A high-speed counter-current chromatography method was developed for the separation and purification of five bioactive coumarins from this plant. The crude coumarins were obtained by ethanol extraction from the dried fruits of Cnidium monnieri (L.) Cusson under sonication. High-speed counter-current chromatography with the two-phase solvent systems n-hexane-ethyl acetate-ethanol-water (5:5:4:6, v/v) and n-hexane-ethyl acetate-ethanol-water (5:5:6:4, v/v) was successfully performed with stepwise elution. The five relatively pure coumarins were obtained from 500 mg of the crude extract in a single run. Their purities were 90.6-98.9%, and the recoveries were 85.7-94.2%.

Chromatography, High Pressure Liquid↗

PubMed1994

TRPM-2 gene expression in normal rat ventral prostate following castration and exposure to diethylstilbestrol, flutamide, MK-906 (finasteride), and coumarin.

TRPM-2, not normally expressed in the rat ventral prostate, has been identified as an important genetic marker of castration-induced apoptotic cell death. It is not known whether other agents capable of causing growth inhibition of the rat ventral prostate also induce TRPM-2 expression. To investigate this further, 270 mature Sprague-Dawley rats were randomized into one of six groups: control, castration, diethylstilbestrol (DES), flutamide, MK-906 (finasteride), or coumarin. Five rats per group were sacrificed on days 1, 3, 5, 7, 10, and 21. Serum testosterone, body weights, and prostate weights were determined at each time point. The ventral prostate was removed and cellular RNA extracted. Northern blot analysis using cDNA probes for TRPM-2 and gamma-actin were performed at each time point. Only DES significantly decreased rat weights. DES and castration reduced serum testosterone to undetectable levels by the next day. Flutamide caused a 3.0- to 4.5-fold increase in serum testosterone above control. Coumarin and MK-906 did not affect serum testosterone levels. DES and castration reduced prostate weights to 20% and 6% of control, respectively, while inducing TRPM-2 expression to a maximum on day 5 of the experiment. DES induced TRPM-2 expression over a longer duration than did castration, suggesting that more than just the decrease of serum testosterone to castrate levels plays a role in the expression of TRPM-2. MK-906, coumarin, and flutamide reduced prostatic weights to a lesser extent (50%, 63%, 71% of control, respectively), but these agents did not induce TRPM-2 expression at any time during the experiment. TRPM-2 expression in the rat ventral prostate does not correlate simply with catabolic effects on the prostate.

Animals↗

PubMed2006

Characterization of an insecticidal coumarin from Boenninghausenia albiflora.

The leaves of Boenninghausenia albiflora afforded an insecticidal coumarin which was identified as murraxocin (7-methoxy-8-[1'-ethoxy-2'-hydroxy-3'-methyl-but-3'enyl]-coumarin) (1), on the basis of extensive 1- and 2-dimensional NMR experiments. This compound has previously been isolated from Murraya exotica but this is the first report of the full (1)H and (13)C data for this compound. This natural product was evaluated against important forest insect pests and was active against Plecoptera reflexa, Clostera cupreata and Crypsiptya coclesalis at different concentrations varying from 1.0% to 5% w/v. In the crude extract 70% mortality was observed, and for compound 1 80% mortality was observed at a concentration of 1.0% w/v. The percentage of insect mortality increased in a dose-dependent manner. Coumarins are poorly studied insecticides and there is potential to exploit this chemically simple group of natural products.

Animals↗

PubMed1996

Effects of coumarin following perinatal and chronic exposure in Sprague-Dawley rats and CD-1 mice.

Coumarin, a naturally occurring substance most frequently used as a fragrance enhancer and stabilizer, was administered in the diet of Sprague-Dawley rats at dose levels of 0, 333, 1000, 2000, 3000, and 5000 ppm or in the diet of CD-1 mice at dose levels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000, and 2000 ppm coumarin were exposed to these dose levels in utero and during the lactational period, then chronically following weaning. Rats in the 3000- and 5000-ppm dose groups and all mice received only postweaning chronic exposure. All male rats were terminated after 104 weeks of postweaning exposure; female rats were terminated after 110 weeks: Male mice were terminated at Week 101 and female mice at Week 109. Among rats, survival was decreased at 333 ppm, but significantly increased among rats in the 3000- and 5000-ppm dose groups. Dramatic dose-related decreases in body weight gain were recorded for rats receiving 2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximum tolerated dose, as indicated by a body weight decrement of greater than 10-15%) was exceeded. Food consumption also was decreased at the three highest dose levels, although body weight decrement was disproportionately large compared to changes in food consumption. Treatment-related decreases in hemoglobin were recorded from Week 6 onward. Minimal treatment-related changes in hematology and clinical chemistry were recorded. Increased liver weights were observed for male and female rats receiving 3000 or 5000 ppm and for females only at 1000 and 2000 ppm. Increased incidences of cholangiofibroma, cholangiocarcinoma, and parenchymal liver cell tumors were observed among male and female rats receiving 5000 ppm. One male rat receiving 3000 ppm developed a cholangiocarcinoma; no tumor increase was observed in males or females at 2000 ppm or below. Coumarin, at a dose clearly exceeding the MTD can, therefore, induce liver tumors in rats, although survival, relative to controls, was increased at the same dose levels. Among mice, a decrease in body weight gain was reported for males in the 1000- and 3000-ppm dose groups during the first 52 weeks of the study. No dose-related abnormalities in clinical signs, clinical pathology, hematology, or gross or microscopic pathology were noted.

Animal Feed↗

PubMed1987

Combined treatment of advanced malignant melanoma with coumarin and cimetidine. A phase II study.

Immunostimulant therapy with coumarin and cimetidine was evaluated in 17 patients with advanced malignant melanoma. Induction therapy with coumarin 100 mg daily was given for 8 weeks, whereupon cimetidine 1000 mg daily was added. No patients had been previously treated with cytotoxic drugs, and all patients had a good performance status. In 16 patients progressive disease was observed, and only 1 patient experienced no change in condition, lasting 30 weeks. We conclude that treatment with this schedule of coumarin and cimetidine is without effect in advanced malignant melanoma.

Adult↗

PubMed1989

Treatment of advanced malignant melanoma with coumarin and cimetidine: a pilot study.

Based on previous results demonstrating that coumarin and cimetidine render objective tumor regressions in renal cell carcinoma, we conducted a pilot study to determine whether these drugs possess activity against malignant melanoma. A total of 22 patients with advanced melanoma received 100 mg coumarin p.o. daily for 14 days; on day 15, cimetidine was added at an oral dose of 300 mg four times daily. Both drugs were continued until progression of disease. In all, 12 patients had previously been treated, but all patients had a favorable performance status. No response was observed in 19 patients. Two patients with a low tumor burden achieved a partial response and a third showed a minor response. There was no toxicity from this regimen. Although coumarin and cimetidine at this dose and schedule did not display significant activity in this study population, further studies are warranted to explore higher doses and focus on patients with relatively low tumor burdens.

Adult↗

PubMed1984

Cytochemistry of the chromatin replication band in hypotrichous ciliated protozoa staining with silver and thiol-specific coumarin maleimide.

A modification of the silver-staining techniques for nucleolar organizing regions (NORs) was used to stain selectively the macronuclear replication bands (RBs) and nucleoli in hypotrichous ciliated protozoa (Euplotes, Stylonychia, and Oxytricha). Silver staining of both types of structures was trypsin-sensitive and DNase I-insensitive, suggesting the involvement of proteins. Silver-staining proteins in the RB were differentially extracted with acid, without any decrease in nucleolar staining. Triton-acid-urea gel electrophoresis of an acid extract of Euplotes macronuclei revealed enhanced silver reaction with a single protein upon selective silver staining. An abundance of thiol groups was also demonstrated in the RBs and nucleoli by the fluorochrome 3-(4-maleimidylphenyl)-7-diethylamino-4-methyl coumarin (coumarin maleimide). Histochemical studies, including blocking thiols with N-ethyl maleimide (NEM), indicated that thiols were not necessary for silver staining, and that proteins in the RBs and nucleoli reacting with coumarin maleimide were not acid extractable.

Animals↗