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PubMed1995

Metabolism of coumarin by precision-cut calf liver slices and calf liver microsomes.

1. The metabolism of 50 microM [3-14C]coumarin has been studied in precision-cut-calf liver slices. 2. The metabolism of 50 microM coumarin to 7-hydroxycoumarin has also been examined in calf, rat, Cynomolgus monkey and human liver microsomal preparations. 3. In precision-cut calf liver slices, [3-14C]coumarin was metabolized to various polar products and to metabolite(s) that bound covalently to calf liver slice proteins. The polar products included 7-hydroxycoumarin (which was extensively conjugated with D-glucuronic acid and/or sulphate), metabolites of the 3-hydroxylation pathway (mainly o-hydroxyphenylethanol and o-hydroxyphenylacetic acid), and unknown metabolites. 4. Coumarin 7-hydroxylase activity was readily detectable in calf, Cynomolgus monkey and human liver microsomes, but only barely detectable in rat liver microsomes. Enzyme activity in calf, Cynomolgus monkey and human liver microsomes was inhibited by 8-methoxypsoralen (methoxsalen) with IC50's (concentration required to produce a 50% inhibition of enzyme activity) ranging from 0.3 to 2.8 microM. 5. These results and those of other studies demonstrate that precision-cut liver slices are a valuable in vitro model system for investigating species differences in xenobiotic metabolism. Coumarin is metabolized in calf liver by various pathways including both 3- and 7-hydroxylation. The inhibition of coumarin 7-hydroxylase activity by 8-methoxypsoralen suggests that calf liver microsomes contain P450A isoenzyme(s) similar to mouse 2A5 and human 2A6.

Animals↗
PubMed2003

Single copy of variant CYP2A6 alleles does not confer susceptibility to liver dysfunction in patients treated with coumarin.

OBJECTIVE: Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration ofcoumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation ofcoumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine. METHODS: The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis. RESULTS: The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior. CONCLUSION: No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

Adult↗
PubMedDate not supplied

Determination of coumarin in fragrance products by capillary gas chromatography with electron capture detection.

A gas chromatographic (GC) method is described for the determination of coumarin in fragrance products. Coumarin was tentatively identified by retention time and confirmed by GC/mass spectrometry. The amount of coumarin was determined by external standard. The method was validated by conducting recovery studies from fortified fragrance products at several concentrations. Recoveries of coumarin ranged from 99 to 110%, with a relative standard deviation of 3.24. The method was used to survey a variety of fragrance products purchased in the metropolitan Washington, DC area, for coumarin. Seventy one percent of the products were found to contain coumarin at concentrations ranging from 0.002 to 0.61%.

Chromatography, Gas↗
PubMed1991

Coumarin (1,2-benzopyrone) enhances DR and DQ antigen expressions by peripheral blood mononuclear cells in vitro.

Coumarin (1,2-benzopyrone) is a natural substance that appears to have some clinical activity against renal cell carcinoma and malignant melanoma. Preliminary evidence from in vitro and in vivo studies suggests that coumarin possesses immunomodulatory activity. It was reported previously that coumarin therapy resulted in augmented DR antigen expression by peripheral blood monocytes in cancer patients. The purpose of the present study was to examine the effects of coumarin on DR and DQ antigen expression by normal donor peripheral blood mononuclear cells in vitro. Using monoclonal antibody labeling techniques and FACS analysis, it was shown that both DR and DQ antigen expression by peripheral blood mononuclear cells were enhanced over controls after 48 hours of exposure to coumarin. While monocytes normally express these antigens, enhanced expression is consistent with an activated state. These results support the hypothesis that coumarin acts, at least in part, through immune augmentation.

Cells, Cultured↗
PubMed1991

Structural function of residue-209 in coumarin 7-hydroxylase (P450coh). Enzyme-kinetic studies and site-directed mutagenesis.

Residue-209 plays a critical role in determining the substrate and product specificity of cytochrome P450coh. In order to investigate further the structural function of residue-209 in coumarin 7-hydroxylase reaction, we measured the enzyme-kinetic properties of wild-type P450coh and its mutants in which residue-209 was substituted with various amino acids. In general, the Km and Vmax values for coumarin increased as the size of residue-209 became smaller and Vmax values decreased. The size of residue-209, therefore, was a principle factor determining Km, Kd, and Vmax values of P450coh. Although the polarity and charge also increased the Km value consistently, they altered Vmax and Kd values in an irregular manner. The substitution of serine for residue-209 increased the Vmax, while the substitution of lysine decreased it. Coumarin 7-hydroxylase activity was inhibited weakly by indan, but competitively and strongly by 2-coumaranone. Moreover, Ki values for the inhibitor were similar to Km values of the corresponding, mutated P450s. The results indicate, therefore, that residue-209 is localized in a proposed substrate-binding sequence 1 which binds to the 2-keto group of coumarin and directs its 7-position toward the sixth ligand of heme. Consequently, the identity of residue-209 determines not only the binding of coumarin in P450coh, but also the other reaction step(s) of coumarin 7-hydroxylation.

Amino Acids↗
PubMed1989

Toxicity of coumarin (1,2-benzopyrone) on human peripheral blood mononuclear cells and human and murine bone marrow progenitor stem cells.

Coumarin (1,2-benzopyrone), in combination with cimetidine, has been subjected to separate clinical trials for the treatment of advanced renal cell carcinoma, malignant melanoma, and non-small cell lung cancer. While objective tumor regressions were observed only in renal carcinoma, no symptomatic or organ dysfunction toxicity was observed in any of the trials. The purpose of the present in vitro study was to determine the concentrations of coumarin and 7-hydroxycoumarin (7-HC) that would be toxic to human peripheral blood mononuclear cells (PB-MNC) and human and murine bone marrow (GM) progenitor stem cells. Coumarin was nontoxic for PB-MNC in concentrations up to 100 micrograms/ml. Concentrations of coumarin or 7-HC greater than or equal to 200 micrograms/ml produced significant suppression of human marrow GM stem cell activity. Coumarin greater than or equal to 25 micrograms/ml produced suppression of murine marrow GM stem cell activity. Differences in human and murine marrow sensitivity probably reflect interspecies differences in metabolism of coumarin. Correlations between toxic concentrations in vitro and maximally achievable serum concentration in vivo in humans await the results of further clinical trials.

Animals↗
PubMed1995

Effect of a combination of coumarin derivatives and rutoside on venous and lymphatic circulations during severe constriction of the caudal vena cava in rabbits.

The effect of a coumarin (CAS 91-64-5) derivatives-rutoside (CAS 153-18-4) combination (Esberiven) has been investigated in an in vivo model of venous hind leg stasis elicited by severe constriction of the caudal vena cava in anesthetized rabbits. The vena cava flow is initially reduced by 80% compared to reference values; then, it significantly declines over time. The venous femoral pressure drops as well as the perfusion pressure whereas the peripheral resistance increases. The popliteal lymph flow gradually slows down after the constriction. Moreover, this venous constriction results in a marked reduction of the right ventricular stroke volume responsible for a left ventricle failure and for the exitus of 30% of the rabbits within 1-3 h post-constriction. A 5-day pretreatment (i.v.) with the coumarin derivatives-rutoside combination at a dose of 4 mg of coumarin derivatives + 200 mg of rutoside/rabbit/day increases the lymph flow but does not suppress the mechanically-induced venous flow decrease. The 6th-day treatment (infusion at the respective doses of 5 mg of coumarin derivatives + 250 mg of rutoside/kg or 10 mg of coumarin derivatives + 500 mg of rutoside/kg) induces a dose-related significant increase of both venous and lymph flows and of the femoral pressure. At the same time, the peripheral venous resistance decreases in a dose-response relationship. Furthermore, after administration of coumarin derivatives and rutoside, the right ventricle stroke volume increases and no death occurs.

Animals↗
PubMed1998

Evidence for metabolic activation of N'-nitrosonornicotine and N-nitrosobenzylmethylamine by a rat nasal coumarin hydroxylase.

Kinetic parameters were determined for the hydroxylation of N'-nitrosonornicotine (NNN), N-nitrosobenzylmethylamine (NBzMA), coumarin, and ethoxycoumarin catalyzed by rat nasal mucosa microsomes. NNN is a tobacco-specific nitrosamine that, in rats, causes tumors in the nasal cavity and esophagus, whereas NBzMA induces tumors in rat esophagus. Both nitrosamines require alpha-hydroxylation to exert their carcinogenic effects. NNN, NBzMA, coumarin, and ethoxycoumarin were all extensively hydroxylated by rat nasal mucosa microsomes. The KM values for the hydroxylation of each substrate were low, ranging between 2 and 5 microM. 2'- and 5'-Hydroxylation of NNN were catalyzed to a similar extent. NBzMA was metabolized predominantly to benzaldehyde, the product of debenzylation, or methylene hydroxylation. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), NNN, and NBzMA were inhibitors of coumarin and ethoxycoumarin hydroxylation. NNN hydroxylation by nasal mucosa microsomes was inhibited by coumarin, ethoxycoumarin, NNK, and NBzMA but not by N-nitrosodimethylamine. 8-Methoxypsoralen, a potent inhibitor of P450 2A6- and 2a5-dependent coumarin hydroxylation in human and mouse liver microsomes, also significantly inhibited NNN activation. The results of this study suggest that the four substrates examined are hydroxylated by closely related P450 enzymes in rat nasal mucosa and that a coumarin hydroxylase metabolizes both NNN and NBzMA.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1989

Mouse steroid 15 alpha-hydroxylase gene family: identification of type II P-450(15)alpha as coumarin 7-hydroxylase.

We identified type II P-450(15)alpha as mouse coumarin 7-hydroxylase (P-450coh). Unlike type I P-450(15)alpha, the other member within the mouse steroid 15 alpha-hydroxylase gene family, type II catalyzed little steroid 15 alpha-hydroxylase activity, yet structurally there were only 11 substitutions between type I and type II P-450(15)alphaS within their 494 amino acid residues (Lindberg et al., 1989), and the N-terminal sequence (21 residues) of P-450coh was identical with that of both P-450(15)alphaS. Induction by pyrazole of coumarin 7-hydroxylase activity correlated well with the increase of type II P-450(15)alpha mRNA in 129/J male and female mice. Pyrazole, on the other hand, was less in males or not effective in females in inducing the 15 alpha-hydroxylase activity and type I P-450(15)alpha mRNA. Expression of type I and II in COS-1 cells revealed that the latter catalyzed coumarin 7-hydroxylase activity at 10 to approximately 14 pmol min-1 (mg of cellular protein)-1. The former, on the other hand, had a high testosterone 15 alpha-hydroxylase but little coumarin 7-hydroxylase activity. It was concluded, therefore, that type II P-450(15)alpha is the mouse coumarin 7-hydroxylase. Identification of type II as the P-450 specific to coumarin 7-hydroxylase activity and characterization of its cDNA and gene, therefore, were significant advances toward understanding the basis of genetic regulation of this activity in mice (known as Coh locus).

Animals↗
PubMed2005

Photodecomposition of organic peroxides containing coumarin chromophore: spectroscopic studies.

The photodecomposition of coumarin-3-t-Bu peroxyester (1) and coumarin-3-carbonyl-m-chlorobenzoylperoxide (2) has been studied using nanosecond and femtosecond spectroscopy to elucidate the nature of transient species involved. Excitation of the coumarin chromophore leads to its singlet excited-state decaying with the rate 9 x 10(9) s(-1) that results from a composite of emission, intersystem crossing, thermal relaxation, and -O-O- bond homolysis. Dissociation of the weak oxygen-oxygen bond proceeds from both triplet and singlet excited states. The nature of this combination of states is predissociative rather than dissociative as demonstrated by the relatively slow rates of oxygen-oxygen bond rupture. The decomposition of 1 and 2 leads to the formation of coumarin-3-carbonyloxyl radical (R1). The later was observed spectroscopically on the nanosecond time scale using both time-resolved FTIR and UV-vis transient techniques. R1 is consumed in two competitive processes: unimolecular decarboxylation and bi-molecular hydrogen atom transfer. The rates of these reactions are 4.3 x 10(5) s(-1) and 1 x 10(6) M(-1) s(-1) respectively. The transition state geometries and energies of decarboxylation of R1 have been determined using DFT calculations and are compared with values for the benzoyloxyl radical. The decarboxylation of R1 proceeds via a transition state in which the carboxyl group is almost perpendicular (dihedral angle 114 degrees) to the plane of the coumarin chromophore. The transition state of the benzoyloxyl radical, in contrast, is flat (0 degrees). The varied transition state energies of the radicals (13.6 kcal/mol for coumarin carboxyl radical vs 8 kcal/mol for benzoyloxyl radical) correlate with different decarboxylation rates of these two species.

Journal Article↗
PubMed1985

Coumarin 7-hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.

Coumarin 7-hydroxylation and other cytochrome P-450-associated enzyme activities were studied in human liver biopsy homogenates and compared with activities in livers of other species. Coumarin 7-hydroxylation is extraordinarily active in human liver biopsy samples in vitro. Activity is lower in mouse, rabbit or guinea pig liver and essentially absent in rat liver. Cytochrome P-450 content and other associated enzyme activities were higher in animals. Coumarin 7-hydroxylation is induced by phenobarbitone in mouse liver, but no significant increase was seen in human or rat liver after exposure to inducers. Correlations amongst coumarin 7-hydroxylase, aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase and cytochrome P-450 are statistically significant (r values from 0.56 to 0.73), but do not permit the conclusion, that the same P-450 form catalyzes all the reactions studied. The correlations between coumarin hydroxylation and antipyrine half-life or clearance are statistically significant, but not good enough for predictive purposes. Coumarin 7-hydroxylase in human liver is inhibited by alpha-naphthoflavone, SKF 525A, metyrapone and aniline.

Animals↗
PubMed2005

Separation and determination of coumarins from Cacalia tangutica by capillary zone electrophoresis.

Capillary zone electrophoresis (CZE), using a 20 mmol/L borate buffer at pH 10.5, was developed for the identification and determination of three coumarins--7-hydroxy-coumarin (HC), 7-hydroxy-8-methoxy-coumarin (HMC) and 7-O-beta-D-glucosyl-coumarin (GC)--in the extracts of the flower of Cacalia tangutica. Regression equations revealed linear relationships (correlation coefficient 0.9986-0.9990) between the corrected peak area (the ratio of peak area to migration time) of each constituent and its concentration. The relative standard deviations (RSD) of the migration time and peak area were 1.45-1.52 and 2.60-3.84% (intra-day), and 1.75-2.22 and 2.90-4.04% (inter-day), respectively. The recoveries of three constituents ranged between 94.5 and 105.6%. The effects of pH value, buffer concentration and applied voltage on the migration behavior of HC, HMC and GC were investigated. The contents of the three active constituents in the flower of Cacalia tangutica were successfully determined within 6 min under the optimum conditions chosen. Moreover, the dissociation constants for three coumarins were also determined by CE.

Coumarins↗
PubMed2006

Toxicity and synergism in the feeding deterrence of some coumarins on Spodoptera frugiperda Smith (Lepidoptera: Noctuidae).

The phagodepression activity of five coumarins (= 2H-1-benzopyran-2-ones), 6-hydroxy-7-isoprenyloxycoumarin (1), 6-methoxy-7-isoprenyloxycoumarin (2), 6,7-methylenedioxycoumarin (3), 5-methoxy-6,7-methylenedioxycoumarin (4), and 6-methoxy-7-(2-hydroxyethoxy)coumarin (5), from the Argentine native herb Pterocaulon polystachyum, was tested against Spodoptera frugiperda (Lepidoptera: Noctuidae) larvae. Two analogs, scopoletin (6) and 2-methoxy-2-methyl-3,4,5,6,7,8-hexahydro-3H-chromen-5-one (7), synthesized in our laboratory, were also evaluated for comparison. The compounds were added to an artificial diet at doses ranging from 50 to 200 microg per g of diet. Natural coumarins induced 100% of phagodepression when 200 microg were added per g of diet. Binary equimolar mixtures of the natural coumarins were phagodepressors against S. frugiperda surpassing the expected additive responses, indicating that these compounds can act synergistically against S. frugiperda larvae. Compounds 1 and 3 (non-methoxylated coumarins), and the equimolar mixture of both, displayed the strongest phagodepression. Additionally, 50 microg/g of 1 and 3 incorporated to the larval diet caused 80 and 50% of pupal mortality, respectively, while a 100 microg/g dose of compounds 2, 4, 6, and 7 produced 60, 50, 10, and 80% pupal mortality, respectively. Larval growing rate during the early larval instars was significantly reduced by treatments with the methylenedioxycoumarins 3 and 4. Coincidentally, the larval period duration was significantly increased by the latter compounds.

Animals↗
PubMed1992

Coumarin inhibits micronuclei formation induced by benzo(a)pyrene in male but not female ICR mice.

Coumarin has been shown to be an effective inhibitor of carcinogenesis in rodents if given before and during the carcinogen treatment. We investigated the possibility that pretreatment with coumarin would inhibit the genotoxicity of benzo(a)pyrene (BP) in ICR mice as indicated by the bone marrow micronucleus test, a widely used in vivo test for genotoxicity. Our studies showed that pretreatment of male mice with doses of coumarin at 65 or 130 mg/kg/day for 1 week (with 1 day of no treatment at midweek) partially inhibited the genotoxicity of BP at a single intraperitoneal dose of 150 mg/kg. Time course experiments showed a decrease in induced micronuclei in the bone marrow at several time points after the BP treatment, thus indicating a true inhibition and not a lag in the induction of micronuclei. However, no inhibition in micronuclei formation was seen in female mice pretreated with the same doses of coumarin. Coumarin treatment alone did not induce micronuclei in either sex. Future studies are needed to analyze the mechanisms responsible for the difference noted between the sexes.

Animals↗
PubMedDate not supplied

Computer-assisted, high-performance liquid chromatography with mass spectrometric detection for the analysis of coumarins in Peucedanum palustre and Angelica archangelica.

A reversed-phase HPLC method with atmospheric pressure chemical ionisation MS detection has been developed for the separation and identification of coumarins in plants of Peucedanum palustre L. (Moench) and Angelica archangelica (L.) var. archangelica. The Turbo Method Development program was utilised to optimise the mobile phase with two organic solvents (acetonitrile and methanol) and two aqueous solutions (1.0% formic acid and 10 mM ammonium acetate). Optimisation of the solvent gradients for the method was performed with the aid of the DryLab program. Analyses were carried out using a Phenomenex Prodigy RP C18 column. Fifty-two peaks (14 of which were associated with coumarins) were separated in 30 min from extracts of P. palustre, and 48 peaks (15 associated with coumarins) from extracts of A. archangelica. A total of 21 different coumarin-type compounds were identified in the aerial and the underground parts of the title plants. Isopimpinellin and pimpinellin were found for the first time in P. palustre and were identified by comparison of retention times and MS data obtained following the analysis of pure standards. This is the first report of the coumarin composition of the umbels of P. palustre.

Angelica archangelica↗
PubMed1990

Treatment of hormone-refractory stage D carcinoma of prostate with coumarin (1,2-benzopyrone) and cimetidine: a pilot study.

The combination of coumarin (1,2-benzopyrone) and cimetidine has been reported to render objective tumor regressions among patients with metastatic renal cell carcinoma and malignant melanoma. Subsequently, a pilot trial was conducted to evaluate this regimen for the treatment of stage D hormone-refractory carcinoma of the prostate. Patients received coumarin 100 mg orally as a single daily dose for 14 days; on day 15 cimetidine 300 mg four times daily was added, and both drugs were continued until progression of disease. Fourteen patients with advanced prostate cancer were treated. Nine patients had evaluable disease only, whereas five patients had both measurable and evaluable disease. All patients had bone metastases. Although there was no objective evidence of tumor regression, three patients (with evaluable disease only) experienced significant improvement in bone pain with decreased analgesic use that persisted until disease progression at 3, 5.5+, and 9 months. Although coumarin caused no symptomatic or organ dysfunction toxicity, one elderly patient experienced reversible mental confusion from cimetidine. Coumarin and cimetidine, at the dose and schedule described, are not effective for the treatment of advanced prostate cancer. However, the results of laboratory investigations suggest that further clinical trials of coumarin, at higher doses, may be warranted for the treatment of this disease.

Aged↗
PubMed1994

Structure-function analysis of CYP2A10 and CYP2A11, P450 cytochromes that differ in only eight amino acids but have strikingly different activities toward testosterone and coumarin.

Cytochrome P450 NMa, which was first identified in this laboratory in rabbit nasal microsomes, is now known to represent two distinct gene products, P450s 2A10 and 2A11. In the present study, chimeric and site-directed mutants of 2A11 were constructed to determine which of the eight different amino acid residues are responsible for the much greater activity of 2A10 toward coumarin and testosterone. Mutation of Arg62 and Asp63 of 2A11 to the corresponding residues in 2A10, or mutation of Thr120 to Ser, as found in 2A10, did not change the activities. However, mutation of Arg62, Asp63, Gln104, Ala117, and Thr120 of 2A11 to the corresponding residues in 2A10 resulted in a protein that is as active as 2A10 in coumarin hydroxylation and approximately half as active as 2A10 in androstenedione formation. Mutation of Arg372 in 2A11 to His, as found in 2A10, resulted in a significant increase in the rate of hydroxylation of testosterone, but not of coumarin. Our findings indicate that the identify of the amino acid at position 104 and/or 117 is important for activity with testosterone and for regioselectivity at the 17 position, as well as for optimal activity with coumarin. In contrast, the identity of the residue at position 372 is important for optimal activity with testosterone but not the regioselectivity at the 17 position and does not influence the activity with coumarin.

Amino Acid Sequence↗
PubMed1989

Indium selectively increases the cytochrome P-450 dependent O-dealkylation of coumarin derivatives in male mice.

Indium pretreatment of rats and mice has been reported to decrease the concentration of cytochrome P-450, thereby reducing the activity of some cytochrome P-450 dependent enzymatic reactions. The present study reveals that pretreatment of C57Bl/6JHan mice of both sexes with one s.c. dose of 120 mg of In2(SO4)3.5 H2O per kg of body weight decreases the concentration of cytochrome P-450 to about 65% of control levels. Neither cytochrome b5 nor NADPH-cytochrome P-450 reductase is affected. Hepatic microsomal ethoxyresorufin O-deethylase activity declines to about 75% of control values. In contrast, with coumarin substrates, a sex dependence in the direction of change is observed: in female mice indium decreases the activity to about 75%, whereas in males it enhances the activity to 140%. Moreover, with 7-(methoxy-14C)coumarin as substrate, indium-pretreated male mice exhale about 180% and females about 65% of 14CO2 compared to the corresponding controls. A close correlation between the in vivo and in vitro effects of indium on the metabolism of the coumarin derivatives is suggested. After isolation and purification of cytochrome P-450, SDS-PAGE indicates in indium-pretreated male mice an intensification of a 48.5 kDa protein band which is decreased in females. Immunological studies using antibodies raised against control female cytochrome P-450 show cross reactivity among all microsomes used in these experiments. High percentages of inhibition occur in microsomes with high molecular activity towards coumarin derivatives. The in vitro kinetics of antibody-inhibited O-deethylation of 7-ethoxycoumarin seems to obey a non- or partial-competitive type of inhibition. Indium pretreatment of mice produces sex-dependent effects on the metabolism of coumarin derivatives.

7-Alkoxycoumarin O-Dealkylase↗