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PubMed2006

Pharmacogenetics-based coumarin therapy.

To reduce the risk of hemorrhage, experts advocate prescribing the anticipated therapeutic dose to patients who are beginning coumarin therapy, but until now there was no accurate way to estimate that dose. Using pharmacogenetics-based coumarin therapy, clinicians can now estimate the therapeutic dose by genotyping their patients for single nucleotide polymorphisms (SNPs) that affect coumarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect coumarin metabolism. Patients with either of two common variants, CYP2C9*2 or CYP2C9*3, metabolize coumarins slowly and are twice as likely to have a laboratory or clinical adverse event, unless their initial coumarin doses are reduced. SNPs in vitamin K epoxide reductase (VKORC1) correlate with coumarin sensitivity. Patients known to be homozygous for a common VKORC1 promoter polymorphism, -1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), should be started on lower coumarin doses than genotype GG patients. By providing an estimate of the therapeutic coumarin dose, pharmacogenetics-based therapy may improve the safety and effectiveness of coumarin therapy.

Aryl Hydrocarbon Hydroxylases↗
PubMed2003

Concomitant coumarin-NSAID therapy and risk for bleeding.

OBJECTIVE: To investigate the risk of bleeding complications during the combined use of coumarin derivatives and nonsteroidal antiinflammatory drugs (NSAIDs) compared with the use of coumarin derivatives alone. SUBJECTS AND METHODS: In this 1-year observational study, the local outpatient anticoagulation office detected all coumarin users with bleeding complications. These patients were sent questionnaires regarding the type and consequences of the bleeding as well as previous NSAID use. The local pharmacists detected patients with concomitant coumarin and NSAID prescriptions (but no bleeding). The relative risk for bleeding due to concomitant coumarin and NSAID use was estimated. RESULTS: During 1 year, 738 hemorrhages were identified in 681 coumarin users. In 12.2% of these cases, an NSAID was involved. In contrast, in the whole population of coumarin users, 2.5% were prescribed an NSAID. Therefore, the relative risk of NSAID use with regard to bleeding complications was 5.8 (95% CI 2.3 to 13.6). CONCLUSIONS: NSAID use during coumarin therapy considerably increases the bleeding risk compared with coumarin therapy alone. Although in daily practice these medications are frequently prescribed concomitantly, our results underscore the contraindication of concomitant use of NSAIDs and coumarin derivatives.

Adult↗
PubMed1991

Effect of inducers of cytochrome P-450 on the metabolism of [3-14C]coumarin by rat hepatic microsomes.

1. The metabolism of [3-14C]coumarin has been studied in rat hepatic microsomes and with two purified cytochrome P-450 isoenzymes. 2. [3-14C]Coumarin was converted by liver microsomes to several polar products including 3- and/or 5-hydroxycoumarin, omicron-hydroxyphenylacetic acid and a major unidentified novel coumarin metabolite. 3. [3-14C]Coumarin was also converted to reactive metabolite(s) as indicated by covalent binding to proteins, and by the depletion of reduced glutathione added to the microsomal incubations. 4. [3-14C]Coumarin metabolism to polar and covalently bound metabolites by rat liver microsomes was induced by pretreatment with phenobarbitone, 3-methylcholanthrene, beta-naphthoflavone, Aroclor 1254 and isosafrole; but not by dexamethasone or nafenopin. 5. The profile of [3-14C]coumarin metabolism to polar products was similar in control and pretreated liver microsomes and in incubations with purified cytochrome P450 IA1 and P450 IIB1 isoenzymes. 6. The results indicate that coumarin is a substrate for isoenzymes of the cytochrome P450 IA and P450 IIB subfamilies. The bioactivation of coumarin by rat hepatic microsomes is postulated to result in the formation of a coumarin 3,4-epoxide intermediate which may rearrange to 3-hydroxycoumarin, be further metabolized to a coumarin 3,4-dihydrodiol, or form a glutathione conjugate.

Animals↗
PubMed1989

Effects of coumarin (1,2-benzopyrone) on lymphocyte, natural killer cell, and monocyte functions in vitro.

We have demonstrated in a pilot study that the combination of coumarin (1,2-benzopyrone) and cimetidine is capable of producing objective antitumor responses in patients with advanced renal cell carcinoma. In a previous study, we used monoclonal antibody labeling techniques to monitor peripheral blood lymphocytes and monocytes in patients with advanced malignancies treated with coumarin and cimetidine. While there was no quantitative alteration in T-lymphocytes, B-lymphocytes, natural killer (NK) cells, or cells bearing Ia antigen, there was an increase in the percentage of CD-14 (M5E2+) monocytes and DR+ monocytes by 2 weeks on therapy that persisted over the 8 weeks of monitoring. Because patients received coumarin for 2 weeks prior to institution of cimetidine, these changes were attributed to coumarin. In this report, we present the results of in vitro studies designed to determine if coumarin alters the functional properties of normal peripheral blood lymphocytes, NK cells, or monocytes. In a standard NK cytolytic assay, coumarin failed to produce any significant alteration in NK activity against K562, ACHN, or Caki-2 cell lines. Coumarin did produce an augmentation of lymphocyte mitogenic response to phytahemagglutinin but not to concanavalin A or pokeweed mitogen. Coumarin produced a modest suppression of superoxide anion and hydrogen peroxide generation by monocytes but not by macrophages. The effect of coumarin on antigen processing of tetanus toxoid by macrophages was examined using normal donor cells. While an augmentation of antigen processing was noted in some normal donors, this was an inconsistent and inconclusive finding. Further studies are required to define the precise effects of coumarin on immune cell populations from both normal subjects and cancer patients.

Antigens↗
PubMedDate not supplied

Structure-activity relationship of coumarins in xanthine oxidase inhibition.

Esculetin(4), umbelliferone(7-hydroxycoumarin)(3) and 7-hydroxy-4-methyl coumarin(8) are strong xanthine oxidase inhibitors (IC50 = 20.91, 43.65 and 96.70 microM respectively). Based on this observation, the structure of 7-hydroxy coumarin(3) plays a very important role in xanthine oxidase (XO) inhibition. The 6-hydroxy group present in the molecule of 7-hydroxy coumarin, e.g. esculetin(4) enhanced the activity, whereas substitution by the 6-methoxy group, e.g. scopoletin (5), reduced the inhibitory effect. Furthermore, 6-glycoside group present in the molecule of 7-hydroxy coumarin, e.g. esculin (6,7-dihydroxy coumarin 6-glucoside)(12) strongly decreased the inhibitory effect as well as scoparone(6), the fully methylated derivative of esculetin (4). In contrast to 7-hydroxy coumarin(3), however, 4-hydroxy coumarin(13) showed only a weak effect on XO inhibition. 4-Substituent present in the molecule of 7-hydroxycoumarin also reduced the activity but the degree of reduction depended on the substituents: 7-hydroxy-4-methylcoumarin (8) < 7-hydroxycoumarin-4-acetic acid (7) < 7-hydroxy-4-trifluoromethylcoumarin (9). Their percent inhibition at 100 microM was 62.47, 38.46 and 26.84% respectively. 8-substituent present in the molecule of 7-hydroxy coumarin (3), such as 7,8-dihydroxy-6-methoxycoumarin(10) and fraxin(7-hydroxy-6-methoxycoumarin 8-glucoside)(11) reduced the activity as compared with scopoletin (5). Their percent inhibition at 100 microM was 18.4 and 6.9% respectively, which indicated that the more bulky the 8-substituted in the structure, the weaker the inhibitory activity on XO. 3,4,8-Trimethyl-7-hydroxycoumarin(14) which substitution by the methyl at 3,4 & 8 in the structure of 7-hydroxycoumarin(3) also reduced the activity as compared with 7-hydroxycoumarin(3). It seems that the double bond in the structure of coumarin(1) played an important role in the activity as compared with coumarin(dihydrocoumarin)(2). The apparent inhibition constants(Ki) of esculetin(4), umbelliferone (3) and 7-hydroxy-4-methylcoumarin(8) were 2.056, 21.683 and 4.86 microM respectively and induced competitive, uncompetitive and a mixed type of inhibition of the enzyme with respect to the substrate xanthine.

Coumarins↗
PubMed1992

Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: effects on coumarin, dicumarol, and testosterone oxidation.

Antibody against purified CYP2A1 recognizes two rat liver microsomal P450 enzymes, CYP2A1 and CYP2A2, that catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone, respectively. In human liver microsomes, this antibody recognizes a single protein, namely CYP2A6, which catalyzes the 7-hydroxylation of coumarin. To examine species differences in CYP2A function, liver microsomes from nine mammalian species (rat, mouse, hamster, rabbit, guinea pig, cat, dog, cynomolgus monkey, and human) were tested for their ability to catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone and the 7-hydroxylation of coumarin. Antibody against rat CYP2A1 recognized one or more proteins in liver microsomes from all mammalian species examined. However, liver microsomes from cat, dog, cynomolgus monkey, and human catalyzed negligible rates of testosterone 7 alpha- and/or 15 alpha-hydroxylation, whereas rat and cat liver microsomes catalyzed negligible rates of coumarin 7-hydroxylation. Formation of 7-hydroxycoumarin accounted for a different proportion of the coumarin metabolites formed by liver microsomes from each of the various species examined. 7-Hydroxycoumarin was the major metabolite (greater than 70%) in human and monkey, but only a minor metabolite (less than 1%) in rat. The 7-hydroxylation of coumarin by human liver microsomes was catalyzed by a single, high-affinity enzyme (Km 0.2-0.6 microM), which was markedly inhibited (greater than 95%) by antibody against rat CYP2A1. The rate of coumarin 7-hydroxylation varied approximately 17-fold among liver microsomes from 22 human subjects. This variation was highly correlated (r2 = 0.956) with interindividual differences in the levels of CYP2A6, as determined by immunoblotting. These results indicate that CYP2A6 is largely or entirely responsible for catalyzing the 7-hydroxylation of coumarin in human liver microsomes. Treatment of monkeys with phenobarbital or dexamethasone increased coumarin 7-hydroxylase activity, whereas treatment with beta-naphthoflavone caused a slight decrease. These results suggest that environmental factors can increase or decrease CYP2A expression in cynomolgus monkeys, which implies that environmental factors may be responsible for the large variation in CYP2A6 levels in humans, although genetic factors may also be important. In contrast to rats and mice, the expression of CYP2A enzymes in cynomolgus monkeys and humans was not sexually differentiated. Despite their structural similarity to coumarin, the anticoagulants dicumarol and warfarin do not appear to be substrates for CYP2A6. The overall rate of dicumarol metabolism varied approximately 5-fold among the human liver microsomal samples, but this variation correlated poorly (r2 = 0.126) with the variation observed in CYP2A6 levels and coumarin 7-hydroxylase activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1970

Involvement of ethylene in responses of etiolated bean hypocotyl hook to coumarin.

Coumarin, at concentrations between 1.0 and 0.1 mm, inhibited red light-induced opening of the etiolated bean hypocotyl hook. In addition, anthocyanin synthesis and geotropic bending were inhibited. Coumarin stimulated ethylene synthesis, and ethylene was shown to mediate the inhibitory actions of coumarin. This conclusion was supported by: (a) the parallel concentration dependence and time sequence of hook closing and ethylene synthesis, (b) the restriction of the bulk of coumarin-induced ethylene production to the curved portion of the hook where opening is expressed, (c) the ability of both coumarin and ethylene to reclose partially opened hooks, and (d) the ability of exogenous ethylene, in the amounts produced by coumarintreated hooks, to duplicate the inhibitory effects of coumarin. There was an increasing stimulation of growth of the straight portion of the hypocotyl hook section as coumarin concentrations were increased from 0.1 to 1.0 mm. This action of coumarin was not duplicated by ethylene and occurred regardless of the presence or absence of added ethylene. The results of this study suggest that many actions of coumarin in growth systems are mediated by ethylene produced in response to the coumarin.

Journal Article↗
PubMed1994

Growth-inhibitory effects of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin on human malignant cell lines in vitro.

Coumarin (1,2-benzopyrone) is a natural substance that has shown antitumor activity in vivo. The major human metabolite of coumarin, 7-hydroxycoumarin (7-HC), is the active form of the drug. While the exact mechanism(s) of action of coumarin is unknown, it has been shown previously that this drug possesses immunomodulatory activity in vitro and in vivo. The present investigations examined the direct (non-immunological) antitumor effects of coumarin and 7-HC in vitro. Both coumarin and 7-HC were found to be growth-inhibitory (cytostatic) for the following human malignant cell lines: A549, ACHN, Caki-2, Dakiki, HS-Sultan, H727, HCT-15, HL-60, K562, LNCaP, PC-3, Du 145 COLO-232, MCF-7 and RP-1788. The growth inhibition was dependent on dose and time and was reversible upon removal of cells from medium containing the drug. Coumarin and 7-HC inhibited [3H]thymidine, [3H]uridine and [3H]leucine incorporation. In a similar fashion, coumarin and 7-HC inhibited the intracellular production of prostate-specific antigen by LNCaP cells. Coumarin and 7-HC stimulated apoptosis in HL-60 cells but not in other cell lines tested. It is concluded that coumarin and 7-HC have direct antitumor (cytostatic) activity as well as immunomodulatory activity. Further information is needed in order to determine which activities are responsible for antitumor activity in vivo.

Apoptosis↗
PubMed1996

Metabolic and analytical interactions of grapefruit juice and 1,2-benzopyrone (coumarin) in man.

OBJECTIVE: Grapefruit juice is known to inhibit mammalian cytochrome P450 isozymes such as CYP3A4. The aim of this study was to investigate the influence of the juice on the fate of coumarin (1,2-benzopyrone) metabolized by CYP2A6 in man. Its potentially inhibitory effect was examined when low and high amounts of grapefruit juice were taken. METHODS: In crossover studies, doses of 10 mg coumarin (Venalot) were given orally to an healthy male volunteer. The drug was taken either with water or with grapefruit juice, at different volumes (300 ml or 4 x 250 ml at intervals of 30 min). Urine samples were collected up to 24 h after dosing. After in vitro hydrolysis they were analysed fluorimetrically for umbelliferone, the metabolite of coumarin, and cumulative excretion curves were established. HPLC and TLC served to identify fluorescent metabolites from the juice. RESULTS: If coumarin is given in water its excretion is complete after 6 h and 70% of the dose is recovered. Grapefruit juice (300 ml) given simultaneously slightly retards the appearance of the fluorescent metabolite in the urine within the first few hours. The recovery of coumarin remains unaffected. One litre of juice enhances the delay and increases the recovery of coumarin to nearly 100%. Respective controls with grapefruit juice alone lead to remarkable excretions of a fluorescent material identified as conjugated scopoletin, which strongly interferes with the analysis of the coumarin experiment. The precursor of scopoletin is widely present at different concentrations in commercially available grapefruit juices. However, the autoinhibition of the juice is correlated neither to the concentration of naringin nor to that of scopoletin. CONCLUSION: Only grapefruit juice given at high doses (1 L) retards the appearance of the main metabolite of coumarin administered orally but increases its recovery. Due to scopoletin formed from the grapefruit juice, experiments especially with coumarin are strongly affected.

Anticoagulants↗
PubMed1992

Metabolism of [3-14C]coumarin to polar and covalently bound products by hepatic microsomes from the rat, Syrian hamster, gerbil and humans.

The metabolism of 0.19 and 2.0 mM-[3-14C]coumarin to polar products and covalently bound metabolites has been studied with hepatic microsomes from the rat, Syrian hamster, Mongolian gerbil and humans. [3-14C]Coumarin was metabolized by liver microsomes from all species to a number of polar products and to metabolite(s) that became covalently bound to microsomal proteins. The polar products included 3-, 5- and 7-hydroxycoumarins, o-hydroxyphenylacetaldehyde and o-hydroxyphenylacetic acid. Coumarin 7-hydroxylation was observed in all species except the rat. With 0.19 mM-[3-14C]coumarin, 7-hydroxycoumarin was the major metabolite in human liver microsomes, whereas in the other species with 0.19 mM substrate and in all species with 2.0 mM substrate o-hydroxyphenylacetaldehyde was the major metabolite. Of the three animal species studied the gerbil most resembled humans as this species also had a high coumarin 7-hydroxylase activity. The administration of Aroclor 1254 to the rat and Syrian hamster induced both microsomal cytochrome P-450 content and [3-14C]coumarin metabolism. With liver microsomes from all species a good correlation between rates of [3-14C]coumarin metabolism and covalent binding was observed at both substrate concentrations. However, in view of the known species difference between the rat and Syrian hamster in coumarin-induced hepatotoxicity, the present data are not consistent with microsomal coumarin metabolite covalent binding being an indicator of potential liver damage.

Acetaldehyde↗
PubMed2002

Studies on the disposition, metabolism and hepatotoxicity of coumarin in the rat and Syrian hamster.

The hepatotoxicity, metabolism and disposition of coumarin has been compared in male Sprague-Dawley rats and Syrian hamsters. The treatment of rats for 12, 24 and 42 weeks with diets containing 0.2 and 0.5% coumarin resulted in hepatotoxicity and increased relative liver weights. While levels of cytochrome P450 (CYP) and CYP-dependent enzymes were decreased, levels of reduced glutathione (GSH) and activities of UDP glucuronosyltransferase, gamma-glutamyltransferase and GSH S-transferase were increased. In contrast, coumarin produced few hepatic changes in the Syrian hamster. Following a single oral dose of 25 mg/kg [3-14C]coumarin, radioactivity was rapidly excreted by the rat and Syrian hamster with the urine containing 63.5 and 89.9%, respectively, and the faeces 38.0 and 12.4%, respectively, of the administered dose after 96 h. The biliary excretion of radioactivity was greater in the rat than in the Syrian hamster. Analysis of 0-24-h urine samples revealed that both species were poor 7-hydroxylators of coumarin. In the rat, treatment with 0.5% coumarin in the diet for 24 weeks was found to increase the urinary excretion of single oral gavage doses of 25 and 300 mg/kg [3-14C]coumarin. The marked species difference in hepatotoxicity between the rat and Syrian hamster observed in this study may be at least partially attributable to differences in coumarin disposition. However, additional studies are required to elucidate the metabolic pathways of coumarin in both species.

Animals↗
PubMed1999

Co-mutagenicity of coumarin (1,2-benzopyrone) with aflatoxin B1 and human liver S9 in mammalian cells.

Coumarin (1,2-benzopyrone), a natural dietary constituent and drug currently under evaluation for treatment of certain cancers and lymphedema, reduces polycyclic aromatic hydrocarbon-induced neoplasms in rodents. Because most rodents metabolize coumarin through 3,4-epoxidation, whereas 7-hydroxylation predominates in humans, their suitability as a model for coumarin effects in humans has been questioned. We examined coumarin chemoprotection against the promutagen and dietary contaminant aflatoxin B1 with human liver S9 bioactivation in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase mutation assay. Coumarin in the absence of aflatoxin B1 was not mutagenic or cytotoxic up to 500 microM. When included with either 1 or 10 microM aflatoxin B1, coumarin produced a dose-dependent increase in mutant frequency and cytotoxicity. At concentrations greater than 50 microM, coumarin stimulated human liver S9 bioactivation of aflatoxin B1 to the mutagenic 8,9-epoxide. This increase was 12- and fivefold at 500 microM coumarin with 1 and 10 microM aflatoxin B1, respectively, compared with incubations with aflatoxin B1 alone. These findings differ from previous results with liver S9 from other species, and indicate that coumarin co-mutagenicity with aflatoxin B1 and human liver S9 is through increased aflatoxin B1 bioactivation.

Aflatoxin B1↗
PubMed2004

Coumarin differentially affects the morphology of different root types of maize seedlings.

The effects of coumarin on the length, diameter, and branching density of different root types in maize seedlings (Zea mays L. cv. Cecilia) were investigated. The maize root system represents a useful model for morphological studies, as it consists of radicle, seminal, and nodal roots whose origin and development are quite different. Maize seedlings were grown in a hydroponic culture for 6 days, and then coumarin (at concentrations of 0, 25, 100, and 400 microM) was added to the nutrient solution. Coumarin inhibited root length, but effects differed depending on the root type. C 1/2 values, representing the coumarin concentration causing a 50% inhibition of the root length, were calculated by nonlinear regression. Six, 1, and 0.25 mM coumarin were sufficient to reduce the radicle, seminal, and nodal root lengths by 50%, respectively. At the highest coumarin concentration, the subapical root zone showed swelling. The degree recorded by average diameter was higher in nodal roots than in seminal and radicle roots. Furthermore, coumarin decreased the number of lateral roots and branching density more in the seminal than in the radicle roots. These results suggest the following order of sensitivity to coumarin: nodal > seminal > radicle roots. The observed spatial effects of coumarin could be ecologically significant, since taprooted species could benefit at the disadvantage of fibrous-rooted species and could modify community composition.

Coumarins↗
PubMed1998

Evaluation of the developmental toxicities of coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin using FETAX.

The developmental toxicities of coumarin and hydroxycoumarin metabolites were evaluated using FETAX. Young X. laevis embryos were exposed to coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. The MAS was also treated with cyclohexene oxide (CHO) to selectively modulate epoxide hydrolase activity. Without the MAS or inhibited MAS, coumarin and 7-hydroxycoumarin were nearly equitoxic, whereas 4-hydroxycoumarin was nearly 2-fold less developmentally toxic than coumarin on an equimolar basis. Addition of the MAS and CIM-MAS increased the developmental toxicities of coumarin and, particularly, 4-hydroxycoumarin. Addition of the CHO-MAS greatly increased the developmental toxicity of coumarin and, especially, 4-hydroxycoumarin. Addition of the ELL- or CO-inhibited MAS did not increase the developmental toxicity of coumarin. However, addition of the intact MAS did not alter the developmental toxicity of 7-hydroxycoumarin. Results from these studies suggested that P-450; specifically ELL-inhibited P-450 (arylhydrocarbon hydroxylase) may have been responsible for increasing the developmental toxicity of coumarin. Furthermore, the increased toxicity of coumarin or 4-hydroxycoumarin following co-incubation with CHO-treated microsomes indicated that highly toxic epoxide intermediates may be produced from oxidative P-450 metabolism and that epoxide hydrolase may play a role in detoxification of the reactive intermediates.

4-Hydroxycoumarins↗
PubMed1991

Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies.

Fifty-four patients with advanced malignancies were treated on this phase I trial of coumarin and cimetidine. The dose of coumarin was escalated, with three patients treated at each dose level, while the cimetidine dose was held constant at 300 mg four times daily. Patients received coumarin alone as a single daily oral dose for 14 days; on day 15, cimetidine was added and both drugs were continued until progression of disease. This trial was initiated with patients receiving coumarin at 400 mg daily and closed at 7 g daily with four of five patients on this dose experiencing nausea and vomiting. Treatment was generally well tolerated over a wide range of coumarin doses. Symptomatic side effects were few, mild, and usually self limited. Side effects included insomnia, nausea, vomiting, diarrhea, and dizziness. Two patients withdrew from therapy because of daily nausea and vomiting. Typically, nausea, vomiting, and dizziness occurred 2.5-3 hours after a dose of coumarin. In most patients, these side effects abated spontaneously with continuation of therapy. There was no significant hematologic or renal toxicity. Hepatotoxicity occurred in only one patient and was manifested by asymptomatic abnormal elevations of serum hepatic transaminases. This toxicity was reversible upon interruption of therapy. Objective tumor regressions were observed in six patients with renal cell carcinoma. Responses occurred at coumarin doses ranging from 600 mg to 5 g daily. Coumarin is a relatively nontoxic, oral, outpatient therapy that warrants further investigations for the treatment of human malignancies. Because of its low toxicity, there is potential for combining coumarin with chemotherapeutic and/or biological agents in an attempt to improve on efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Growth until puberty after in utero exposure to coumarins.

Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the child's skeletal development.

Abnormalities, Drug-Induced↗
PubMed1997

Inhibition of coumarin 7-hydroxylase activity in human liver microsomes.

Nine organic solvents and 47 commonly used P450 substrates and inhibitors were examined for their effects on coumarin 7-hydroxylase (CYP2A6) activity in human liver microsomes. Of the nine organic solvents examined (final concentration 1%, v/v), only methanol did not inhibit the 7-hydroxylation of coumarin (0.5 to 50 microM) by human liver microsomes. Dioxane and tetra-hydrofuran, which are structurally related to coumarin, were the most inhibitory solvents examined. Although the rates of coumarin 7-hydroxylation varied enormously among nine samples of human liver microsomes and cDNA-expressed CYP2A6 (Vmax = 179 to 2470 pmol/ mg protein/min), the Km for coumarin 7-hydroxylation was fairly constant (ranging from 0.50 to 0.70 microM). The following chemicals caused little or no inhibition of CYP2A6 as defined by a Ki > 200 microM: caffeine, chlorzoxazone, cimetidine, dextromethorphan, diazepam, diclofenac, erythromycin, ethinylestradiol, ethynyltestosterone, fluconazole, furafylline, furfural, hexobarbital, itraconazole, mephenytoin, methimazole, metronidazole, naringenin, naringin, nifedipine, norfloxacin, norgestrel, orphenadrine, quinidine, papaverine, phenacetin, pyrimethamine, ranitidine, spironolactone, sulfaphenazole, sulfinpyrazone, testosterone, tolbutamide, troleandomycin, and warfarin. In other words, these chemicals, at a final concentration of 100 microM, failed to inhibit CYP2A6 when the concentration of coumarin was equal to Km (0.50 microM). The following chemicals were classified as strong inhibitors of CYP2A6 (defined by Ki < 200 microM): clotrimazole, diethyldithiocarbamate, ellipticine, ketoconazole, 8-methoxypsoralen, 4-methylpyrazole, metyrapone, miconazole, alpha-naphthoflavone, nicotine, p-nitrophenol, and tranylcypromine. The potency with which each chemical inhibited the 7-hydroxylation of coumarin was independent of which sample of human liver microsomes was studied. One of the most potent inhibitors of coumarin 7-hydroxylase was 8-methoxypsoralen (methoxsalen), which was determined to be a mechanism-based inhibitor (suicide substrate) of CYP2A6 (k(inactivation) 0.5 min-1). With the exception of 8-methoxypsoralen, preincubation of human liver microsomes and NADPH with the aforementioned inhibitors did not increase their ability to inhibit CYP2A6. The most potent competitive inhibitor of CYP2A6 was tranylcypromine (Ki = 0.04 microM). Several of the chemicals that strongly inhibited CYP2A6, such as ketoconazole and tranylcypromine, are often used with the intention of selectively inhibiting human P450 enzymes other than CYP2A6. The results of this study underscore the need for a systematic evaluation of the specificity of commonly used P450 inhibitors.

Adult↗
PubMed2000

Quinolizin-coumarins as physical enhancers of chemiluminescence during lipid peroxidation in live HL-60 cells.

We investigated whether physical enhancers of low-level chemiluminescence-coumarin laser dyes C-314, C-334, and C-525--may be used to monitor interactions of lipid peroxyl radicals during lipid peroxidation in live cells. We present data demonstrating that two quinolizin-substituted coumarins--C-525 and C-334--can be integrated into HL-60 cells and successfully used as physical enhancers of chemiluminescence induced by the lipid soluble azo-initiator 2,2'-azobis(2,4-dimethyl-valeronitrile) (AMVN). Coumarins did not inhibit AMVN-induced peroxidation of membrane phospholipids in HL-60 cells, and no consumption of these coumarins occurred in the course of AMVN-induced oxidative stress. Redox status, evaluated by intracellular GSH content, remained unchanged after treatment with the coumarins. tert-Butyl hydroperoxide and cumene hydroperoxide (more hydrophilic oxidants) induced a lower chemiluminescence signal with both coumarins. Viability of HL-60 cells was not affected by coumarins both in the presence and in the absence of oxidants. Based on these results we conclude that quinolizin-substituted coumarins represent a promising class of physical enhancers of chemiluminescence for monitoring free radical peroxidation in live cells.

Azo Compounds↗