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PubMed1999

Lack of effect of coumarin in women with lymphedema after treatment for breast cancer.

BACKGROUND: Lymphedema of the arms can be a serious consequence of local and regional therapy in women with breast cancer. Coumarin has been reported to be effective for the treatment of women with lymphedema; we undertook a study in which we attempted to replicate those findings. METHODS: We studied 140 women with chronic lymphedema of the ipsilateral arm after treatment for breast cancer. The women received 200 mg of oral coumarin or placebo twice daily for six months and then the other treatment for the following six months. The end points of the study consisted of the volume of the arm (calculated from measurements of hand and arm circumference) and the answers on a questionnaire completed by the patient about symptoms potentially related to lymphedema. RESULTS: The volumes of the arms at 6 and 12 months, were virtually identical, regardless of whether coumarin or placebo was given first. After six months, the average volume of the affected arm increased by 21 ml during placebo treatment and 58 ml during coumarin treatment (P=0.80). In addition, answers to patient-completed questionnaires were similar in the two treatment groups. After six months only 15 percent of the women in the coumarin group and 10 percent of those in the placebo group reported that the study medication had helped a moderate or large amount (P=0.19). Coumarin was well tolerated, except that it resulted in serologic evidence of liver toxicity in 6 percent of the women. CONCLUSIONS: Coumarin is not effective therapy for women who have lymphedema of the arm after treatment for breast cancer.

Adult↗
PubMed2005

Pharmacogenomics: its role in re-establishing coumarin as treatment for lymphedema.

Although there remains some significant controversy regarding the use and benefits of coumarin (5,6-benzo-alpha pyrone), it would seem that targeted appropriate and monitored use of the drug does have a significant role in the treatment of lymphedemas. The particular benefits are its cost and ease of administration. Given today's demands for high level investigative clinical trials, it would be virtually impossible to conduct a study large enough to make any significant conclusions about hepatotoxic effects. However, it seems without doubt that the majority of studies conducted thus far suggest that coumarin (and other benzopyrones, i.e., the ruto-sides, which do not have hepatotoxic effects and which are often discussed in aggregate with coumarin) is effective in treating lymphedema, particularly when used in conjunction with complex physical therapy. The use of pharmacogenomics could significantly lower the risk of coumarin-associated hepatotoxicity, by targeting the use of coumarin to those with functional CYP2A6. Further research in this area will be required to re-evaluate the cost- benefit ratio and to determine the potential for the reintroduction of coumarin as a potent treatment for lymphedema. The perceived negative image of coumarin should not be allowed to carry across to the other benzopyrones, as they still confer a significant benefit in the management of lymphedemas.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Study of the in vitro cytotoxic potential of natural and synthetic coumarin derivatives using human normal and neoplastic skin cell lines.

A selection of natural and synthetic coumarin compounds, including the hydroxylated and nitrated derivatives, were assessed for their cytotoxic potential using the microculture 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cellular viability. For the first time this study utilized both human skin malignant melanocytes (SK-MEL-31) and normal human skin fibroblastic cells (HS613.SK), allowing identification of those coumarin derivatives that are selectively toxic. Coumarin was found to exhibit comparatively low toxicity in both cell types, while 7-hydroxycoumarin (7-OHC) and coumarin had similar activity in SK-MEL-31 cells. The entire series of hydroxylated coumarins were considerably more toxic in HS613.SK than in SK-MEL-31 cells. Novel synthetic nitrated coumarins, 6-nitro-7-hydroxycoumarin (6-NO2-7-OHC) and 3,6,8-nitro-7-hydroxycoumarin (3,6,8-NO2-7-OHC), were shown to be significantly more toxic to SK-MEL-31 than HS613.SK cells. In the malignant melanocyte skin cell line (SK-MEL-31) the cytotoxic effects of these nitro-derivatives were shown to be dose and time dependent. Therefore, the cytotoxic potential of coumarins appears to be highly dependent on the nature and position of the functional group. In addition, nitration of 7-OHC produced compounds that were cytotoxic to malignant melanocytes, suggesting that these nitro-derivatives may have a chemotherapeutic role in the future.

Cell Division↗
PubMed2005

Probing the binding of the coumarin drugs using peptide fragments of DNA gyrase B protein.

Bacterial DNA gyrase, has been identified as the target of several antibacterial agents, including the coumarin drugs. The coumarins inhibit the gyrase action by competitive binding to the ATP-binding site of DNA gyrase B (GyrB) protein. The high in vitro inhibitory potency of coumarins against DNA gyrase reactions has raised interest in studies on coumarin-gyrase interactions. In this context, a series of low-molecular weight peptides, including the coumarin resistance-determining region of subunit B of Escherichia coli gyrase, has been designed and synthesized. The first peptide model was built using the natural fragment 131-146 of GyrB and was able to bind to novobiocin (K(a) = 1.8 +/- 0.2 x 10(5)/m) and ATP (K(a) = 1.9 +/- 0.4 x 10(3)/m). To build the other sequences, changes in the Arg(136) residue were introduced so that the binding to the drug was progressively reduced with the hydrophobicity of this residue (K(a) = 1.3 +/- 0.1 x 10(5)/m and 1.0 +/- 0.2 x 10(5)/m for Ser and His, respectively). No binding was observed for the change Arg(136) to Leu. In contrast, the binding to ATP was not altered, independently of the changes promoted. On the contrary, for peptide-coumarin and peptide-ATP complexes, Mg(2+) appears to modulate the binding process. Our results demonstrate the crucial role of Arg(136) residue for the stability of coumarin-gyrase complex as well as suggest a different binding site for ATP and in both cases the interactions are mediated by magnesium ions.

Adenosine Triphosphate↗
PubMed1995

Competitive inhibition of coumarin 7-hydroxylation by pilocarpine and its interaction with mouse CYP 2A5 and human CYP 2A6.

1. We have shown earlier that pilocarpine strongly inhibits mouse and human liver coumarin 7-hydroxylase activity of CYP 2A and pentoxyresorufin O-deethylase activity of CYP 2B in vitro. Since pilocarpine, like coumarin, contains a lactone structure we have studied in more detail its inhibitory potency on mouse and human liver coumarin 7-hydroxylation. 2. Pilocarpine was a competitive inhibitor of coumarin 7-hydroxylase in vitro both in mouse and human liver microsomes although it was not a substrate for CYP 2A5. Ki values were similar, 0.52 +/- 0.22 microM in mice and 1.21 +/- 0.51 microM in human liver microsomes. 3. Pilocarpine induced a type II difference spectrum in mouse, human and recombinant CYP 2A5 yeast cell microsomes, with Ka values of 3.7 +/- 1.6, 1.6 +/- 1.1 and 1.5 +/- 0.1 microM, respectively. 4. Increase in pH of the incubation medium from pH 6 to 7.5 increased the potency of inhibition of coumarin 7-hydroxylation by pilocarpine. 5. Superimposition of pilocarpine and coumarin in such a way that their carbonyls, ring oxygens and the H-7' of coumarin and N-3 of pilocarpine overlap yielded a common molecular volume of 82%. 6. The results indicate that pilocarpine is a competitive inhibitor and has a high affinity for mouse CYP 2A5 and human CYP 2A6. In addition the immunotype nitrogen of pilocarpine is coordinated towards the haem iron in these P450s.

Animals↗
PubMed2003

A comparison of US and Norwegian regulation of coumarin in tobacco products.

OBJECTIVE: This paper examines policy processes regarding why the USA and Norway have not regulated coumarin in tobacco. DESIGN: A qualitative analysis of all tobacco industry documents regarding coumarin since the 1950s from the 1998 US Master Settlement Agreement and subsequent legal settlements. Additional data were collected from newspaper reports, general internet search engines, journal articles, scholarly reports, court cases, statutes, regulations, and informal correspondence with tobacco control experts in Norway. MAIN OUTCOME MEASURE: An overview, summary, and analysis of all documents related to coumarin. RESULTS: In the USA from 1954 until 1985 when coumarin was reportedly removed from domestic cigarettes, but not from pipe tobacco until 1996, and not at all from imported Indian bidi cigarettes, regulatory efforts were stymied. In Norway, from 1973 to the present, the tobacco industry has never disclosed whether its tobacco products contain coumarin. In both the USA and Norway, the extreme delay and lack of vigorous evidence gathering and significant remedies were caused by tobacco industry assertions that revealing tobacco additives was a violation of trade secrets, and by weak regulatory authority and efforts to regulate coumarin. CONCLUSION: Vigorous and expeditious regulatory investigations and remedies for harmful additives in tobacco, such as coumarin, can protect the public health. Astute insider and outsider political advocacy by health advocates is required to hold elected officials and civil servants publicly accountable for failing to enact disclosure laws and to engage in effective regulatory efforts.

Coumarins↗
PubMed2004

Natural and synthetic coumarin derivatives with anti-inflammatory/ antioxidant activities.

Several natural products with a coumarinic moiety have been reported to have multiple biological activities. It is to be expected that, in a similar way to isomeric flavonoids, coumarins might affect the formation and scavenging of reactive oxygen species (ROS) and influence processes involving free radical-mediated injury. Coumarin can reduce tissue edema and inflammation. Moreover coumarin and its 7-hydroxy-derivative inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. Natural products like esculetin, fraxetin, daphnetin and other related coumarin derivatives are recognised as inhibitors not only of the lipoxygenase and cycloxygenase enzymic systems, but also of the neutrophil-dependent superoxide anion generation. Due to the unquestionable importance of coumarin derivatives considerable efforts have been made by several investigators, to prepare new compounds bearing single substituents, or more complicated systems, including heterocyclic rings mainly at 3-, 4- and/or 7-positions. In this review we shall deal with naturally occurring or synthetically derived coumarin derivatives, which possess anti-inflammatory as well as antioxidant activities.

Animals↗
PubMed1992

Metabolism of coumarin by rat, gerbil and human liver microsomes.

1. o-Hydroxyphenylacetaldehyde was the major metabolite of coumarin (1 mM) in rat, gerbil and human liver microsomes. 2. Treatment of rats with phenobarbitone (PB) or beta-naphthoflavone increased the o-hydroxyphenylacetaldehyde formed. 3-Hydroxycoumarin was the other main metabolite produced by rat liver microsomes. 3. Liver microsomal metabolism of coumarin in gerbil was extensive with 3-, 5-, 6-, 7- and 8-hydroxycoumarins, and 3,7- and 6,7-dihydroxycoumarins produced, in addition to o-hydroxyphenylacetaldehyde. The profile of the hydroxy metabolites was altered by in vivo treatment of gerbils with cytochrome P-450 inducers, but there was no increase of coumarin metabolism. 4. Coumarin was metabolized by human liver microsomes to o-hydroxyphenylacetaldehyde, 7-hydroxycoumarin, 3-hydroxycoumarin, and trace amounts of 5-, 6- and 8-hydroxycoumarins. 5. At low substrate concentrations (0-10 microM) hepatic microsomal metabolism of coumarin in gerbil resembled that in man, with 7-hydroxycoumarin being a major metabolite. However, the production of o-hydroxyphenylacetaldehyde was greater in gerbil than human liver microsomes. 6. At higher substrate concentrations (1 mM) metabolism of coumarin by liver microsomes from PB-treated gerbils most closely resembled that by human liver microsomes. 7. The gerbil would appear to be a more appropriate animal model than rat for studies to assess the toxicological hazard of coumarin for man.

Adolescent↗
PubMed1996

Ethnic-related differences in coumarin 7-hydroxylation activities catalyzed by cytochrome P4502A6 in liver microsomes of Japanese and Caucasian populations.

1. Interethnic differences in cytochrome P4502A6 (CYP2A6) levels and coumarin 7-hydroxylation activities were determined in liver microsomes of 30 Japanese and 30 Caucasians. 2. Although CYP2A6 levels and coumarin 7-hydroxylation activities varied very significantly in the 60 human samples examined, both CYP2A6 levels and coumarin 7hydroxylation activities were found to be higher in Caucasian than Japanese population. 3. Interestingly, eight of the 30 Japanese examined showed very low or undetectable levels of coumarin 7-hydroxylation activities as well as of CYP2A6 in liver microsomes. All of the Caucasians, however, had significant CYP2A6 levels and variable 7-hydroxylation activities. 4. Kinetic analvsis of coumarin 7-hydroxylation activities in liver microsomes of various human samples suggested that although there were 260-fold differences in Vmax's in 10 human samples examined, the Km's were very similar (2.1 + or - 107 mu M); a value consistent with that obtained (1.2 mu M) with purified CYP2A6 in reconstituted system. 5. The results suggest that CYP2A6 is actually involved in the 7-hydroxylation of coumarin in human liver microsomes, and that interethnic differences in coumarin 7-hydroxylation activities in Japanese and Caucasian population may be ascribed to the differences in expression of CYP2A6 protein.

Antibodies↗
PubMed1999

Genetic variation in the metabolism of coumarin in mouse liver.

The metabolism of 50 microM [3-14C] coumarin to polar products separated by high performance liquid chromatography (HPLC) and covalently bound metabolites in liver microsomes was compared in a series of inbred strains of mice. Coumarin metabolism to total polar products was higher in female than male mice. In all strains, the coumarin 3,4-epoxidation pathway was the major route of metabolism with o-hydroxyphenylacetaldehyde (o-HPA) as the major metabolite. However, in females, there was a major strain difference in the degree of metabolism to coumarin 7-hydroxylase with DBA/2 and 129 having high 7-hydroxycoumarin formation, CBA/Ca having intermediate levels and the other strains low levels. The differences between the strains was much less pronounced in the male mice. There was also evidence for strain variation in metabolism in the quantities of a number of other coumarin metabolites as detected by HPLC analysis of incubate extracts. However, this variation was of a quantitative nature and relatively small. The metabolism of B6C3F1 hybrid mice, in which coumarin had been identified as carcinogenic in a long-term cancer bioassay, was qualitatively similar to that of the other genotypes. The DBA/2 mouse has been suggested as a model for the metabolism of coumarin in humans. The pattern of metabolism found in this strain is different from most other strains. However, the pattern found for all the mouse strains, including DBA/2, differed appreciably from the profiles for other species including humans in the extent of 7-hydroxylation.

Animals↗
PubMed2002

Risk factors for bleeding in patients taking coumarins.

Coumarins (e.g., warfarin) are used for the treatment and prophylaxis of venous and arterial thromboembolism. Unfortunately, their use is limited by bleeding. In deciding whether to initiate coumarin therapy, the therapeutic benefits must be weighed against the potential risk of bleeding for each individual patient. The major determinants of coumarin-related bleeding are the intensity of anticoagulant effect as measured by the International Normalized Ratio, patient characteristics, concomitant use of other drugs, and the length of anticoagulant therapy. At the initiation of coumarin therapy, the risk factors for bleeding can be identified by the COUMARINS acronym and by one of the bleeding prediction models. During ongoing therapy with coumarins, the risks and benefits of therapy should be reassessed periodically. This article reviews the current evidence for the prediction and prevention of coumarin-related bleeding.

Anticoagulants↗
PubMed1992

Coumarin congeners as antidepressants.

3-Carboethyl coumarin (I) was converted to coumarin 3-acid hydrazide (II). This on reaction with appropriate aldehyde yielded 3-arylidino amino coumarin (III). Compound III on diazotisation and reaction with ferric chloride yielded the corresponding formazans viz. 3-substituted phenyl azoarylidino, amido coumarins (IVa1-a10) and oxadiazoles viz. 2-aryl-5-(3-coumarinyl)-1,3,4-oxadiazoles (Va1-a3), respectively. Simultaneously 3-carboethyl coumarin on hydrolysis gave 3-carboxy coumarin (VI) which on reaction with aryl amine in methylene chloride yielded 3-(N-aryl)amido coumarin (VIIa1-a3). The compounds were screened for their antidepressant activity against a tricyclic antidepressant (imipramine). Compounds IVa4, IVa5 and IVa9 exhibited activity better than imipramine with no toxicity (ALD50 greater than 1000 mg/kg) but IVa5 showed some side effects.

Amphetamine↗
PubMed1989

Effect of coumarin on the normal rat prostate and on the R-3327H prostatic adenocarcinoma.

Coumarin, the parent compound of warfarin, has been observed to stimulate macrophages, increase phagocytosis, and induce changes in lymphocyte-mitogen responsiveness in cancer patients. Coumarin has been reported to have antitumor activity in human melanomas and renal cancer when used in conjunction with the H-2 antagonist, cimetidine. We have observed that coumarin has antiprostatic activity in rats. When coumarin was given to mature rats at a dose of 40 mg/kg, a significant decrease in the size of the prostate, seminal vesicles, and testes was observed. Testosterone levels were unchanged or slightly elevated, consistent with an antiandrogenic-like activity. Similarly, coumarin significantly inhibited the androgen-induced increase in prostatic size when administered to castrated rats receiving testosterone. Coumarin given to rats bearing the R-3327H androgen-sensitive, prostate-derived tumor decreased the size of the primary tumor. The effect was greater than that produced by castration. Coumarin is worthy of further consideration as an agent for use in controlling the normal and abnormal growth of the prostate.

Adenocarcinoma↗
PubMed1998

Color vision deficits during laser lithotripsy using safety goggles for coumarin green or alexandrite but not with holmium:YAG laser safety goggles.

PURPOSE: Laser lithotripsy requires urologists to wear laser eye protection. Laser eye protection devices screen out specific light wavelengths and may distort color perception. This study tests whether urologists risk color confusion when wearing laser eye protection devices for laser lithotripsy. MATERIALS AND METHODS: Urologists were tested with the Farnsworth Dichotomous Test for Color Blindness (D-15) and the Farnsworth-Munsell 100-Hue Test (FM-100) without (control) and with laser eye protection devices for coumarin green, alexandrite and holmium:YAG lasers. Error scores were tabulated. The pattern of color deficits was characterized with confusion angles, confusion index (C-index), scatter index (S-index) and color axes. Laser eye protection devices were tested with spectrophotometry for spectral transmittance and optical density. RESULTS: The D-15 transposition errors (mean plus or minus standard deviation) for control, holmium:YAG, alexandrite and coumarin green laser eye protection were 0 +/- 0, 0 +/- 0, 0.3 +/- 0.5 and 6.4 +/- 1.6, respectively (p = 0.0000001). The FM-100 error scores (mean plus or minus standard deviation) were 20 +/- 15, 20 +/- 14, 91 +/- 32 and 319 +/- 69, respectively (p = 0.0001). The confusion index scores indicated a mild color confusion for the alexandrite and pronounced color confusion for the coumarin green laser eye protection. The confusion angles and scatter indexes mimicked a congenital blue-yellow deficit for coumarin green laser eye protection. Color axes showed no significant deficits for control or holmium:YAG laser eye protection in any subject, red-green axis deficits in 3 of 6 tested with alexandrite and blue-yellow axis deficits in 12 of 12 tested with coumarin green (p < 0.001). Spectrophotometry showed that laser eye protection for coumarin green blocks light less than 550 nm., alexandrite blocks light greater than 650 nm. and holmium:YAG blocks light greater than 825 nm. CONCLUSIONS: Laser eye protection for coumarin green causes pronounced blue-yellow color confusion, whereas alexandrite causes mild red-green color confusion among urologists, holmium:YAG causes no significant color confusion compared to controls. The differences are explained by laser eye protection spectrophotometry characteristics and visual physiology.

Adult↗
PubMed1996

Inhibition of zeta-crystallin by Coumarins: a structure-activity study.

A structure-activity study was carried out to determine the important groups of coumarin derivatives in inhibiting the oxidoreductase activity of the camel lens zeta-crystallin. Coumarin, 4-hydroxycoumarin, 7-hydroxy-4-methylcoumarin, dicoumarol, and warfarin were screened for their inhibitory effect on zeta-crystallin activity. The sequence of potency for the inhibitors was dicoumarol > 4-hydroxycoumarin > warfarin > > coumarin. 7-Hydroxy-4-methylcoumarin was ineffective as an inhibitor. Only dicoumarol, 4-hydroxycoumarin, and warfarin were found to inhibit the oxidoreductase activity in micromolar ranges. All tested inhibitors seem to act in reversible and time-independent manner. Concentration causing 50% inhibition of the enzyme activity (IC50 value) was 34 microM for dicoumarol, 76 microM for 4-hydroxycoumarin, and approximately 515 microM for warfarin, while 1 mM coumarin showed less than 10% inhibition. Kinetic analysis revealed inhibition of camel lens zeta-crystallin by coumarin derivatives to occur in a competitive manner with respect to dichlorophenolindophenol (DCIP) as an electron acceptor and uncompetitive manner with respect to NADPH as an electron donor. The Ki values were found to be 16 microM for dicoumarol, 40 microM for 4-hydroxycoumarin, and 220 microM for warfarin. The structure-activity relationship of coumarin derivatives indicates that the phenolic hydroxyl group at the C-4 position in the coumarin skeleton is important for the maximal inhibition.

2,6-Dichloroindophenol↗
PubMed2005

Synthesis, antiproliferative, and vasorelaxing evaluations of coumarin alpha-methylene-gamma-butyrolactones.

Certain coumarin alpha-methylene-gamma-butyrolactones were synthesized and evaluated for antiproliferative and vasorelaxing activities. These compounds were synthesized via alkylation of hydroxycoumarins 2a-f followed by oxidation and the Reformatsky-type condensation. The results of this study are as follows (1) for the vasorelaxing activity, coumarin-7-yl alpha-methylene-gamma-butyrolactone 6d, with an IC50 value of 9.4 microM against pig coronary arterial contraction induced by KCl, is a more active vasorelaxant than its coumarin-4-yl counterpart 6a and its gamma-methyl congener 1. A methyl group substituted at C-4 of the coumarin-7-yl moiety reduced the vasorelaxing effect (6d vs 6e) while the 3,4,8-trimethyl derivative 6f was inactive. (2) For the antiproliferative activity, coumarin-4-yl alpha-methylene-gamma-butyrolactone 6a, which exhibited the most potent antiproliferative activity on the growth of MCF7, NCI-H460, and SF-268 with IC50 values of 6.97, 14.68, and 8.36 microM, respectively, is more cytotoxic than its coumarin-7-yl counterpart 6d and the 6,7-dimethyl derivative 6b. For the coumarin-7-yl derivatives, 6d is more active than its gamma-methyl congener 1, indicating that substitution at the gamma-position decreased cytotoxicity.

4-Butyrolactone↗
PubMed2006

Local environments of coumarin dyes within mesostructured silica-surfactant nanocomposites.

The local environments surrounding dye molecules were studied with use of coumarin dyes in a mesostructured silica-surfactant nanocomposite, which was formed in a porous alumina membrane by a surfactant-templated method and has an average pore diameter of 3.4 nm. Coumarin dyes, such as coumarin 480 (C480), coumarin 343 (C343), and propylamide coumarin 343 (PAC343), were extracted into the silica-surfactant nanocomposite and time-resolved fluorescence spectra of these dyes were examined. C480 and C343 show slow dynamic Stokes shifts and the decay curve can be fitted by a biexponential function. The decay-time constants obtained from the fitting are almost identical for C480 and C343: 0.87 and 7.5 ns for C480, and 0.86 and 7.6 ns for C343. In contrast to these two coumarin dyes, short decay-time constants (0.50 and 4.8 ns) were obtained for PAC343 in the silica-surfactant nanocomposite. These results indicate that the local environments of C480 and C343 are almost identical but different from that of PAC343. By considering the origin of the dynamic Stokes shift and the mesostructure of the silica-surfactant nanocomposite, the location and microenvironment of coumarin dyes within the silica-surfactant nanocomposite are discussed.

Journal Article↗
PubMed1985

Selective induction of coumarin 7-hydroxylase by pyrazole in D2 mice.

Pyrazole, was given to DBA/2N (D2), C57BL/6N (B6) and AKR/N mice to study its effects on hepatic drug metabolism. A decrease in the total amount of microsomal cytochrome P-450 as well as in the activities of ethylmorphine demethylase and benzo[a]pyrene hydroxylase was found. On the other hand ethoxycoumarin de-ethylase was increased 1.5-2.5-fold (depending on the strain of mouse) and coumarin 7-hydroxylase as much as sevenfold (but only in D2 mice) after pyrazole treatment. This increase was much higher than that caused by phenobarbital, the only well known inducer of coumarin 7-hydroxylase. By reconstituting the mono-oxygenase complex after purification of cytochrome P-450 we found a 40-fold increase in coumarin 7-hydroxylase and eightfold increase in ethoxycoumarin de-ethylase after pyrazole treatment. This was found only in D2 mice. An antibody previously developed against a cytochrome P-450 fraction from the the D2 strain with a high coumarin 7-hydroxylase activity inhibited the microsomal coumarin 7-hydroxylase almost 100% after pyrazole pretreatment of the animals. In the case of control or phenobarbital-treated mice the inhibition was somewhat weaker. With the reconstituted mono-oxygenase complex the inhibition of coumarin 7-hydroxylase was almost 100% both for control and pyrazole-treated D2 mice. The data indicate that pyrazole causes an induction of the microsomal monooxygenase complex different from that caused by phenobarbital or 3-methylcholanthrene and selective for coumarin 7-hydroxylation or 7-ethoxycoumarin de-ethylation. This induction was strong in D2, weak in B6 and absent in AKR/N mice.

Animals↗