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PubMed1986

Coumarin induced acral skin necrosis associated with hereditary protein C deficiency.

Hemorrhagic skin necrosis of the toes was observed in a patient with heterozygous protein C deficiency (protein C:Ag 32% and protein C activity 30%) on the 4th day of coumarin treatment overlapping with effective intravenous anticoagulation with heparin. Family studies revealed protein C deficiency in two sisters of the proposita without a history of thromboembolic disease. Immunologic studies in the proposita at the time of coumarin necrosis revealed slight depression of complement factor C4 and the presence of immune complexes. The present case and review of the literature show that the pathogenetic mechanism leading to coumarin necrosis in patients with protein C deficiency seems not yet to be fully understood.

Adult↗

PubMed1994

Treatment with coumarin to prevent or delay recurrence of malignant melanoma.

Both coumarin (1,2-benzopyrone) and warfarin (4-hydroxycoumarin) have been shown to prevent the recurrence of malignant melanoma. Their action is macrophage-dependent and the dosage is critical. In 1984 a multicentre, prospective, randomised, double-blind trial of coumarin, given as a daily 50-mg dose for 2 years after surgery in patients with high-risk melanoma, was started. the patients had lesions greater than 1.70 mm thick and TNM stage IB or stage II disease. To date there are 4 recurrences in the coumarin-treated group of 13 patients, and 10 recurrences in the placebo-treated group of 14 patients (P < 0.01). There were no toxic effects.

Chemotherapy, Adjuvant↗

PubMed1976

The influence of coumarin on blood levels of radio labelled protein and radio labelled poly-vinyl-pyrrolidone in thermally injured rats.

The evidence presented in this paper suggests that coumarin is a RES stimulator. An enhanced removal of both RPP and radio RPVP was observed beginning at or before 30 minutes and lasting up to 6 hours. Over this time, RPP removal was enhanced by an average of 40%, while RPVP removal was enhanced by 60%. Since RPVP is non-metbabolizable, its levels may be a more accurate estimate of the stimulatory effect of coumarin. This evidence fits in well previous results which have suggested that coumarin may increase the number of phagocytic cells. Other results have shown enhancement of protein lysis by 74% over similar periods, while enhanced protease activity levels of 50% have been observed to accompany this.

Animals↗

PubMed1978

Coumarin toxicity in different strains of mice.

The general toxic effects of coumarin, as well as coumarin hepatotoxicity were found to be less in DBA/2J mice than in CH3/HeJ mice. These results are discussed in the context of a strain-specific coumarin metabolism and indicate the need for suitable animal models to assess the toxicity of a given substance in man.

Animals↗

PubMed1992

Coumarins: macrophage proteinase production and pinocytosis.

Coumarins, which are thought to stimulate macrophage proteinase activity, have been advocated for the treatment of high protein oedemas, such as obstructive lymphoedema. In experiments with cultured murine macrophages, coumarin and 7-hydroxycoumarin (10(-3) or 10(-4) M) had no significant effect on plasminogen-activator activity, plasminogen-independent fibrinolytic activity or pinocytosis. Although no in vitro effect on macrophage proteinase activity was found, it is possible that coumarins activate other cell types in vivo and thus effectively treat lymphoedema.

Animals↗

PubMed2000

CYP2A6 genetic polymorphisms and liver microsomal coumarin and nicotine oxidation activities in Japanese and Caucasians.

Genotypes of CYP2A6, namely CYP2A6(*)1 (wild-type), CYP2A6(*)2, and CYP2A6(*)3, were examined in liver DNA of 39 Japanese and 43 Caucasians using two-step polymerase chain reaction (PCR) methods. We first amplified a DNA fragment (1725 bp) located between near middle of exon 1 and end of exon 4 of the CYP2A6 gene and further amplified using a forward primer 't' or 'mut' (middle of exon 3) and a reverse primer 'E3R' (middle of intron 3) for the detection of CYP2A6(*)2-genetic polymorphism. The 1725 bp fragment was also used for the amplification between exon 3 and near middle of intron 3 of the CYP2A6 gene and the fragment thus obtained digested with XcmI or DdeI to detect and confirm the CYP2A6(*)2- and CYP2A6(*)3-types, respectively. Only one DNA sample from a Japanese origin (J18) was not amplified by CYP2A6-specific primers; liver microsomes from this individual had very low activity of coumarin 7-hydroxylation and were devoid of protein(s) immunoreactive to anti-CYP2A6 antibody. Thus, this individual was suggested to be due to the gene deletion in CYP2A6. By analyzing the remaining 38 Japanese and 43 Caucasians, we found that there were no cases of CYP2A6(*)3-type polymorphism in the samples examined in this study, and no cases of CYP2A6(*)2-type polymorphism in the Japanese samples. Of Caucasians studied two individuals were classified into heterozygous CYP2A6(*)1/(*)2-type. Liver microsomal coumarin 7-hydroxylation activities in these two Caucasians were found to be lower than those of the other 41 Caucasians. Kinetic analysis showed that two CYP2A6(*)1/(*)2 individuals had a very low ratio of V(max) to K(m) for nicotine C-oxidation as well as coumarin 7-hydroxylation in liver microsomes, compared with those of homozygous CYP2A6(*)1-type. These results suggest that among 39 Japanese and 43 Caucasians examined one Japanese is classified to be CYP2A6 gene deletion and two Caucasians are heterozygous CYP2A6(*)1/(*)2-genotype. Thus the race-related differences in the occurrence of CYP2A6 genetic polymorphisms were supported.

Aryl Hydrocarbon Hydroxylases↗

PubMed1996

Comparison of the toxicity of allyl alcohol, coumarin and menadione in precision-cut rat, guinea-pig, cynomolgus monkey and human liver slices.

The toxicity of allyl alcohol, coumarin and menadione has been studied in precision-cut liver slice cultures. Liver slices were prepared from male Sprague-Dawley rats, male Dunkin-Hartley guinea-pigs and from samples of Cynomolgus monkey and human liver using a Krumdieck tissue slicer. The liver slices were cultured with the test compounds for 24 h in a dynamic organ culture system. Toxicity was assessed by measurement of protein synthesis, potassium content and the MTT assay. At the concentrations examined, menadione produced marked toxicity in liver slices from all four species, whereas rat liver slices were less susceptible to allyl alcohol toxicity. Coumarin produced concentration-dependent toxic effects in rat and guinea-pig liver slices, whereas Cynomolgus monkey and human liver slices were relatively resistant, especially at low coumarin concentrations. At some concentrations of the test compounds examined, the MTT assay appeared to be a less sensitive indicator of toxicity than either protein synthesis or potassium content. These results demonstrate the usefulness of precision-cut liver slices for assessing species differences in xenobiotic-induced toxicity.

1-Propanol↗

PubMed1997

The character of inhibition of the metabolism of 1,2-benzopyrone (coumarin) by grapefruit juice in human.

OBJECTIVE: Constituents of grapefruit juice are known to interfere with mammalian cytochrome P450 isozymes such as intestinal CYP3A4 and hepatic CYP2A6, lowering the biotransformation of drugs and increasing their bioavailability. The aim of this study was to investigate whether the presence of naringin is demanded for the inhibition of the coumarin 7-hydroxylase in man or other compounds are responsible for it. METHODS: In cross-over studies, doses of 10 mg coumarin, together with combinations of grapefruit juice, water and naringin, were given orally to one healthy male volunteer, We investigated increasing amounts of grapefruit juice, keeping the volume of liquid constant at 1 L; increasing doses of naringin given in water; increasing amounts of juice, keeping the dose of naringin constant; or increasing doses of naringin, keeping the amount of juice constant. Urine samples were collected up to 24 h after dosing and 7-hydroxycoumarin was quantified fluorimetrically in urine hydrolysates after HPLC separation to determine the excretion rates. RESULTS: While increasing amounts of grapefruit juice delay the excretion of 7-hydroxycoumarin by 2 h, increasing doses of naringin in water up to twofold (i.e. naringin content of 2 L grapefruit juice) do not cause any alteration in the time course of excretion. Experiments with increasing amounts of juice, keeping the dose of naringin constant, indicate that the inhibitory potency of small amounts of grapefruit juice can be amplified by naringin. The same is true when the ratio between juice constituents and naringin is enhanced up to threefold by adding naringin. CONCLUSION: As naringin alone is ineffective, the inhibitory effect of grapefruit juice on the metabolism of coumarin is caused by at least one compound other than naringin. The persistency of the primary inhibitor not identified yet can obviously be modulated by the naring(en)in-system.

Anticoagulants↗

PubMed1991

O-hydroxyphenylacetaldehyde: a major novel metabolite of coumarin formed by rat, gerbil and human liver microsomes.

A major novel coumarin metabolite was isolated from rat hepatic microsomal incubations by high-performance liquid chromatography. In the presence of a rat liver cytosolic fraction and NADH it was rapidly metabolized to O-hydroxyphenylethanol. The metabolite co-chromatographed with an authentic sample of O-hydroxyphenylacetaldehyde and its identity was confirmed by mass spectral analysis. The formation of O-hydroxyphenylacetaldehyde from coumarin was NADPH-dependent. It was the major metabolite formed by rat, gerbil and human liver microsomes at a coumarin concentration of 1mM.

Acetaldehyde↗

PubMed1991

The protein kinase inhibitor, K-252a, decreases elicitor-induced Ca2+ uptake and K+ release, and increases coumarin synthesis in parsley cells.

An elicitor preparation from fungal cell walls known to induce coumarin synthesis in suspension-cultured parsley cells also elicits a rapid and transient Ca2+ uptake, K+ release and external alkalinization, and increases uptake of 45Ca2+ into the cells. The latter three responses were inhibited by the protein kinase inhibitor K-252a at 0.2 microM. Elicitor-induced coumarin synthesis, a process which requires gene activation, was greatly enhanced by K-252a. These results suggest that protein phosphorylation might be involved in the initial steps of signal transduction as well as in the long-term induction of coumarin synthesis.

Biological Transport↗

PubMed1984

Antithrombin III in patients with acute deep vein thrombosis during heparin treatment (subcutaneous and intravenous) and during and after treatment with oral coumarins.

The antithrombin III (AT-III) concentration was studied in 98 patients with symptomatic acute deep-vein thrombosis. All patients were initially treated with heparin randomly by subcutaneous injections or by continuous infusions. Then the patients were treated with coumarins during one or six months. The AT-III concentration was estimated daily during heparin treatment and repeatedly during the first year. The mean AT-III concentration decreased progressively 25% during 5 days of heparin treatment regardless of whether heparin was given intravenously or subcutaneously. The mean AT-III concentration during coumarin treatment was higher than after coumarin treatment. Eleven patients developed recurrent thromboembolic episodes during the follow-up period. The mean AT-III concentration in these patients was not lower than in the patients without recurrences.

Adult↗

PubMed1995

Comparison of the metabolism of 7-ethoxycoumarin and coumarin in precision-cut rat liver and lung slices.

The metabolism of 7-ethoxycoumarin and [3-(14)C]coumarin was compared in precision-cut rat liver and lung slices. The lung slices were prepared using an agarose gel instilling technique enabling the production of tissue cylinders followed by lung slices employing a Krumdieck tissue slicer. Both 50 microM 7-ethoxycoumarin and 50 microM [3-(14)C]coumarin were metabolized by rat liver and lung slices. 7-Ethoxycoumarin was converted to 7-hydroxycoumarin (7-HC) which was conjugated with both D-glucuronic acid and sulfate. 7-HC sulfate was the major metabolite formed by both liver and lung slices. [3-(14)C]Coumarin was metabolized by rat liver and lung slices to both polar products and to metabolite(s) that bound covalently to tissue slice proteins. The polar products included unidentified metabolites and 3-hydroxylation pathway products, with only very small quantities of 7-HC being formed. These results demonstrate that precision-cut lung slices are a useful model in vitro system for studying the pulmonary metabolism of xenobiotics. Moreover, the precision-cut tissue slice technique may be employed for comparisons of hepatic and extrahepatic xenobiotic metabolism.

Animals↗

PubMed1994

Comparison of in vivo and in vitro rat hepatic toxicity of coumarin and methyl analogues, and application of quantitative morphometry to toxicity in vivo.

The rat hepatic toxicity of coumarin and methyl analogues (3-,4-methyl coumarin and 3,4-dimethylcoumarin) has been determined in vivo and in vitro (freshly-isolated cells). Coumarin at a dose of approximately 1 mmol/kg produced clear histological evidence of centrilobular necrosis, while the methyl analogues at an equivalent dose were much less toxic. By use of a systematic random sampling protocol and quantitative morphometry it was determined that there was a lobar variation in the extent of hepatic damage but that this exhibited random inter-animal variation. The order of cytotoxicity in vitro was identical to that observed in vivo. In hepatocytes depleted of glutathione the toxicity of all four compounds was increased. This was particularly marked for the 3-methyl analogues, such that the order of toxicity was different to that observed in vivo and in hepatocytes not depleted of glutathione.

Animals↗

PubMed1992

DNA gyrase activities from Rhodobacter capsulatus: analysis of target(s) of coumarins and cloning of the gyrB locus.

Bacterial DNA gyrase is composed of two subunits, gyrase A and B, and is responsible for negatively supercoiling DNA in an ATP-dependent manner. The coumarin antibiotics novobiocin and coumermycin are known inhibitors of bacterial DNA gyrase in vivo and in vitro. We have cloned, mapped, and partially sequenced Rhodobacter capsulatus gyrB which encodes the gyrase B subunit that is presumably involved in binding to coumarins. DNA gyrase activities from crude extracts of R. capsulatus were detected and it was shown that the R. capsulatus activity is (1) inhibited by novobiocin and coumermycin, (2) ATP-dependent and, (3) present in highly aerated and anaerobically grown cells. We previously observed that when R. capsulatus coumermycin-resistant strains are continuously recultured on media containing coumermycin they sometimes acquired mutations in hel genes (i.e., cytochromes c biogenesis mutations). We discuss the possibility that coumarins may inhibit cytochromes c biogenesis as a second target in R. capsulatus via hel (i.e., a putative ATP-dependent heme exporter).

Adenosine Triphosphate↗

PubMed1994

Late neurological, cognitive and behavioural sequelae of prenatal exposure to coumarins: a pilot study.

Neurological, cognitive and behavioural development were assessed in a group of 21, 8- to 10-year old children whose mothers took coumarins during pregnancy. Findings were compared with those in a group of 17 control children. The study was performed to test whether it is feasible to carry out a reliable retrospective study of late effects of prenatal exposure to coumarins. This turned out to be the case. In this small pilot study, no statistical significant differences were found between the study and control group, nevertheless a few findings were remarkable. One child showed severe neurological abnormalities, which may be due to prenatal exposure to oral anticoagulants. The children with the lowest scores on the neurological assessment and the lowest IQ-scores, were found in the exposed group. Obviously, the number of children in this study is too small to conclude if there has been definite effects from coumarin, but these results indicate that a large follow-up study is required. In the present paper, we have shown that such a study is feasible.

Administration, Oral↗

PubMed1995

Antipyrine, coumarin and glipizide affect n-acetylation measured by caffeine test.

The effect of various treatments on acetylation status measured by caffeine metabolites was investigated in 17 subjects with non-insulin dependent diabetes mellitus (NIDDM). The test drugs, caffeine (200 mg), antipyrine (20 mg/kg) and coumarin (5 mg), were given simultaneously, and urinary 5-acetylamino-6-formyl-amino-3-methyluracil/1-methylxanthine (AFMU/1X) molar ratio was measured before and after 8 weeks of therapy. The urinary AFMU/1X molar ratio decreased (p < 0.05) after 8 weeks of therapy with glipizide (2.5 mg), but remained unaltered in those treated with placebo or those who self-monitored blood glucose (SMBG) by glucometer. Antipyrine and coumarin decreased (p < 0.05) the AFMU/1X molar ratio both in diabetics and healthy volunteers. Our data demonstrate that glipizide, antipyrine and coumarin may interfere with the classification of acetylator status measured by caffeine metabolites.

Acetylation↗

PubMed2004

The effect of substitution patterns on the release rates of opioid peptides DADLE and [Leu(5)]-enkephalin from coumarin prodrug moieties.

A coumarin-based prodrug system has been developed in our laboratory for the preparation of esterase-sensitive prodrugs of amines, peptides, and peptidomimetics. The drug release rates from this prodrug system were found to be dependent on the structural features of the drug moiety. The effect of the phenyl ring substitutions on the release kinetics of such prodrugs of model amines was examined recently and it was found that appropriately positioned alkyl substituents on the phenyl ring could help to facilitate the release. Aimed at further understanding the structure-release rate relationship of the coumarin-based cyclic prodrugs, we synthesized and examined a series of substituted coumarinic acid derivatives of opioid peptides, DADLE, and [Leu(5)]-enkephalin.

Coumarins↗

PubMed2006

Structure-activity relationship of natural and synthetic coumarins inhibiting the multidrug transporter P-glycoprotein.

A set of 32 natural and synthetic coumarins were tested in order to evaluate their activity on human leukemic cells (K562/R7) overexpressing P-glycoprotein (P-gp). Their ability to reduce the P-gp-mediated drug efflux of daunorubicin out of cells was evaluated at 10 microM. Four natural compounds, previously isolated from Calophyllum dispar (Clusiaceae) and substituted by a common alpha-(hydroxyisopropyl)dihydrofuran moiety, exhibited a significant inhibitory effect on P-gp when compared to the positive control cyclosporin A. A 3D-quantitative structure-activity relationship (3D-QSAR) analysis of the coumarins was performed using the biological results obtained by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of P-gp. Results showed a favorable electrostatic and steric volume, like the alpha-(hydroxyisopropyl)dihydrofuran moiety, beside C(5)-C(6) or C(7)-C(8) positions. In addition, the analysis revealed an important hydrophobic, neutral charge group, like phenyl, in position C(4) on the coumarinic ring.

ATP Binding Cassette Transporter, Subfamily B, Mem↗