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Oxidation of the alcohol dehydrogenase inhibitor pyrazole to 4-hydroxypyrazole by microsomes. Effect of cytochrome P-450 inducing agents.

Pyrazole and its analogues are widely used to inhibit alcohol dehydrogenase and to block the metabolism of ethanol. Experiments were conducted to demonstrate that pyrazole is oxidized to 4-hydroxypyrazole by isolated rat liver microsomes. A HPLC procedure employing UV and electrochemical detection was developed for the separation and quantitation of 4-hydroxypyrazole. Pyrazole metabolism was NADPH-dependent, sensitive to inhibition by carbon monoxide, and was depressed in the presence of other substrates such as aniline or ethanol. Prior treatment of rats with either pyrazole or 4-methylpyrazole resulted in an increase in pyrazole oxidation to 4-hydroxypyrazole by microsomes. Increases were observed when rates were expressed either per mg of protein or per nmol of P-450. Microsomes from pyrazole- and 4-methylpyrazole-treated rats had Km values for pyrazole of about 0.29 and 0.14 mM, respectively, and Vmax values of about 0.5 and 0.7 nmol of 4-hydroxypyrazole per min per mg of protein, respectively. Chronic consumption of ethanol for 24 days resulted in an increase in pyrazole oxidation (per mg of protein and per nmol of P-450) as compared to pair-fed controls. By contrast, phenobarbital treatment lowered the rate of production of 4-hydroxypyrazole. Treatment with 3-methylcholanthrene resulted in an increase in pyrazole oxidation when rates were expressed per mg of protein, but not per nmol of P-450. These results show that pyrazole is oxidized to 4-hydroxypyrazole by microsomes in a P-450-dependent manner and that this metabolism can be increased by certain inducers, e.g. pyrazole, 4-methylpyrazole, and chronic ethanol treatment.

Alcohol Dehydrogenase↗
PubMed1988

Oxidation of pyrazole to 4-hydroxypyrazole by intact rat hepatocytes.

4-Hydroxypyrazole has been identified as a major metabolite found in the urine of rats and mice after in vivo administration of pyrazole, a potent inhibitor of alcohol dehydrogenase and of ethanol metabolism. The locus and the enzyme systems responsible for the oxidation of pyrazole have not been identified. In the current report, isolated hepatocytes from fed rats were shown to oxidize pyrazole to 4-hydroxypyrazole. An HPLC procedure employing UV and electrochemical detection was utilized to separate and quantify the 4-hydroxypyrazole. The apparent Km for pyrazole by intact hepatocytes was about 2 mM, whereas the apparent Vmax was about 0.06 nmol 4-hydroxypyrazole per min per mg liver cell protein. The production of 4-hydroxypyrazole was inhibited by carbon monoxide and metyrapone, as well as by competitive drug substrates such as aniline or aminopyrine. These results implicate a role for cytochrome P-450 in the oxidation of pyrazole by the hepatocytes. Ethanol was an effective inhibitor of pyrazole oxidation. Hepatocytes were also isolated from rats treated with acetone and 4-methylpyrazole, to attempt to evaluate whether pyrazole oxidation is induced. The rate of 4-hydroxypyrazole production by hepatocytes after acetone and 4-methylpyrazole treatment was actually lower than that of controls. Kinetic assays suggested the presence of an endogenous inhibitor (perhaps the inducer itself) in the induced hepatocytes. In contrast, hepatocytes isolated from rats fasted for 48 hr showed a 2-fold increase in the oxidation of pyrazole to 4-hydroxypyrazole. The Km for pyrazole was the same in hepatocytes from fasted and fed rats, whereas Vmax was increased after fasting. The locus and enzyme system responsible for the oxidation of pyrazole to 4-hydroxypyrazole, and the site of sensitivity to ethanol, appears to be the cytochrome P-450 system of the hepatocyte.

Animals↗
PubMed1984

Structure of the liver alcohol dehydrogenase-NAD+-pyrazole complex as determined by 15N NMR spectroscopy.

The structures of the liver alcohol dehydrogenase (LADH)-NAD+-pyrazole and LADH-NAD+-4-ethylpyrazole complexes were investigated by 15N nuclear magnetic resonance (NMR) spectroscopy. 15N chemical shifts were obtained for 15N-labeled inhibitors and 15N-labeled coenzyme bound in the ternary enzyme complexes. The structures of the two inhibitor complexes appear to be very similar. 15N NMR studies of model pyrazole-zinc chloride complexes were carried out to determine the effect of zinc complexation on pyrazole chemical shifts. The N1 nicotinamide chemical shift of the coenzyme of the LADH-NAD+-pyrazole complex demonstrates that the NAD+ is converted to a dihydronicotinamide derivative in the complex. The N1 chemical shift of the pyrazole in the ternary complex is consistent with covalent bond formation between pyrazole N1 and the nicotinamide ring of the coenzyme. The N2 chemical shift of the pyrazole in the ternary complex indicates that the nucleus of this nitrogen is about 40 ppm more shielded than those of the N2 nitrogens of typical pyrazoles. Such shielding is expected as the result of direct complexation of N2 to the active-site zinc. Shift comparisons with zinc-pyrazole complexes indicate a high degree of inner-sphere coordination of the pyrazole N2 to the active-site zinc in the ternary complex.

Alcohol Dehydrogenase↗
PubMed2005

Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole.

Elevated LPS and elevated cytochrome P-450 2E1 (CYP2E1) in liver are two major independent risk factors in alcoholic liver disease. We investigated possible synergistic effects of the two risk factors in causing oxidative stress and liver injury. Sprague-Dawley rats were injected intraperitoneally with pyrazole (inducer of CYP2E1) for 2 days, and then LPS was injected via tail vein. Other rats were treated with pyrazole alone or LPS alone or saline. Eight hours later, blood was collected and livers were excised. Pathological evaluation showed severe inflammatory responses and necroses only in liver sections from rats in the pyrazole plus LPS group; blood transaminase levels were significantly elevated only in the combination group. Activities of caspase-3 and -9 and positive terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining were highest in the LPS alone and the LPS plus pyrazole group, with no significant difference between the two groups. Lipid peroxidation and protein carbonyls in liver homogenate as well as in situ superoxide production were maximally elevated in the LPS plus pyrazole group. Levels of nitrite plus nitrate and inducible nitric oxide (NO) synthase (iNOS) content were comparably elevated in LPS alone and the LPS plus pyrazole group; however, 3-nitrotyrosine adducts were elevated in the combined group but not the LPS group. It is likely that LPS induction of iNOS, which produces NO, coupled to pyrazole induction of CYP2E1 which produces superoxide, sets up conditions for maximal peroxynitrite formation and production of 3-nitrotyrosine adducts. CYP2E1 activity and content were elevated in the pyrazole and the LPS plus pyrazole groups. Immunohistochemical staining indicated that distribution of CYP2E1 was in agreement with that of necrosis and production of superoxide. These results show that pyrazole treatment enhanced LPS-induced necrosis, not apoptosis. The enhanced liver necrosis appears to involve an increase in oxidative and nitrosative stress generated by the combination of LPS plus elevated CYP2E1 levels.

Animals↗
PubMed1988

Characterization and identification of a pyrazole-inducible form of cytochrome P-450.

In vivo administration of the alcohol dehydrogenase inhibitor pyrazole induces a cytochrome P-450 isozyme. The pyrazole-inducible cytochrome P-450 has been purified from rat livers to electrophoretic homogeneity and its biochemical, spectral, and immunological properties characterized. The final preparation had a specific content of 11 nmol of cytochrome P-450/mg of protein. A single band with an apparent molecular weight of 52,000 was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The absolute spectrum of the isolated pyrazole cytochrome P-450 displayed peaks at 648 and 396 nm, suggestive of a high spin cytochrome. The ethylisocyanide difference spectrum exhibited two maxima, one at 457 nm, the other at 428 nm. Pyrazole and dimethyl sulfoxide produced binding spectra with the purified P-450, with peaks at 425 or 419 nm and troughs at 390 or 386 nm, respectively. K8 values for dimethyl sulfoxide and pyrazole were 21 and 0.04 mM, respectively. The catalytic activity of the pyrazole cytochrome P-450 was elevated with aniline and dimethylnitrosamine (low Km) but not with aminopyrine, benzphetamine, ethoxycoumarin, or ethoxyresorufin as substrates. An antibody against pyrazole cytochrome P-450 recognized a 52,000 molecular weight protein upon reaction with saline microsomes. The intensity of the immunoblot was increased when microsomes isolated from pyrazole, 4-methylpyrazole-, acetone-, or chronic ethanol-treated rats were utilized, but not after phenobarbital or 3-methylcholanthrene treatment. Homology at the amino terminus of 19 amino acids was observed between pyrazole P-450 and the isoniazid-inducible P-450j. Based upon the above catalytic, spectral, and immunological properties, it appears that pyrazole induces a form of cytochrome P-450 which is identical to that induced by ethanol and isoniazid.

Amino Acids↗
PubMed1990

Increased oxidation of p-nitrophenol and aniline by intact hepatocytes isolated from pyrazole-treated rats.

Induction of cytochrome P-450 IIE1 by pyrazole has been shown in a variety of studies with isolated microsomes or reconstituted systems containing the purified P-450 isozyme. Experiments were conducted to document induction by pyrazole in intact hepatocytes by studying the oxidation of p-nitrophenol to 4-nitrocatechol or of aniline to p-aminophenol. Hepatocytes prepared from rats treated with pyrazole for 2 days oxidized p-nitrophenol or aniline at rates which were 3- to 4-fold higher than saline controls. To observe maximal induction in hepatocytes, it was necessary to add metabolic substrates such as pyruvate, sorbitol or xylitol, which suggests that availability of the NADPH cofactor may be rate-limiting in the hepatocytes from the pyrazole-treated rats. Carbon monoxide inhibited the oxidation of p-nitrophenol and aniline by hepatocytes from the pyrazole-treated rats and controls, demonstrating the requirement for cytochrome P-450. The oxidation of both substrates by the hepatocyte preparations was inhibited by a variety of agents that interact with and are effective substrates for oxidation by P-450 IIE1 such as ethanol, dimethylnitrosamine, pyrazole and 4-methylpyrazole. Microsomes isolated from pyrazole-treated rats oxidized aniline and p-nitrophenol at elevated rats compared to saline controls. These results indicate that induction by pyrazole of the oxidation of drugs which are effective substrates for P-450 IIE1 can be observed in intact hepatocytes. The extent of induction and many of the characteristics of aniline or p-nitrophenol oxidation observed with isolated microsomes from pyrazole-treated rats can also be found in the intact hepatocytes.

Aniline Compounds↗
PubMed2001

Triarylpyrazoles with basic side chains: development of pyrazole-based estrogen receptor antagonists.

Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.: Mortenson, D. S.: Stauffer, S. R.; Aron, Z. D.: Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERalpha subtype in terms of binding affinity and agonist potency (Stauffer, S. R.: Coletta, C. J.: Tedesco. R.: Sun, J.: Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ERalpha) with 20-fold higher affinity than to ERbeta. In cell-based transcription assays, pyrazole 5 was an antagonist on both ERalpha and ERbeta, and it was also more potent on ERalpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ERalpha-raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene.

Binding Sites↗
PubMed1992

Pyrazole, an alcohol dehydrogenase inhibitor, has dual effects on N-methyl-D-aspartate receptors of hippocampal pyramidal cells: agonist and noncompetitive antagonist.

Electrophysiological and biochemical studies demonstrated that pyrazole, an inhibitor of alcohol dehydrogenase and a proposed therapeutic agent for treatment of alcoholic intoxication, activated and blocked the N-methyl-D-aspartate (NMDA) receptor and did not interact significantly with the end-plate nicotinic acetylcholine receptor (AChR). Pyrazole, at concentrations as low as 0.5 microM, applied to outside-out patches excised from the membrane of cultured rat hippocampal neurons, elicited single-channel currents of 48 pS which were blocked by DL-2-amino-5-phosphorovaleric acid, a competitive antagonist of NMDA. In addition, binding studies showed that pyrazole displaced 1-(cis-2-carboxypiperidine-4-yl)methyl-1-phosphoric acid from the agonist recognition site of the NMDA receptor in a concentration-dependent manner and enhanced the binding of (+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine to this complex. These data indicate that pyrazole is an agonist at NMDA receptors. However, at higher concentrations, open and burst times as well as the frequency of single-channel currents activated by pyrazole were reduced significantly, a finding which suggests that this compound is also an open channel blocker. In agreement with these results, it was shown biochemically that pyrazole was able to stimulate influx of Ca++ into rat brain microsomes via NMDA receptors and on the other hand to block the influx of Ca++ induced by NMDA. Pyrazole was unable to affect the neuromuscular transmission of frog sartorius muscle-sciatic nerve preparations. Additionally, pyrazole did not interact either with the agonist recognition site or with noncompetitive sites of the AChR. However, this drug had a very weak agonist-like action on the AChR of the Torpedo electric organ, most likely via binding sites different from those described previously for acetylcholine. Therefore, the therapeutic efficacy of pyrazole may be related at least in part to its effects on the NMDA receptor. Furthermore, this compound, because of the small size and rigidity of its molecular structure, becomes a promising drug for the study of the NMDA receptor. Indeed its use may allow a better understanding of the physiological and pathological processes involving this receptor.

Alcohol Dehydrogenase↗
PubMed1999

Self-assembly of NH-pyrazoles via intermolecular N-H.N hydrogen bonds.

The crystal structures of two NH-pyrazole derivatives forming intermolecular N-H.N hydrogen bonds are reported: 5-methyl-4-(3-methylpyrazol-5-yl)pyrazol-3-ol, C(8)H(10)N(4)O (P1), and 3-methyl-5-dihydro-1H-naphtho[1,2-d]pyrazole hemihydrochloride, C(12)H(12)N(2).-C(12)H(13)N(2)(+).Cl(-) (P2). 26 other structures are surveyed in order to obtain a deeper insight into the ways NH-pyrazoles self-assemble by means of intermolecular N-H.N hydrogen bonds in molecular crystals. A limited number of compounds form chains or dimers via homonuclear N(+)-H.N positive-charge-assisted hydrogen bonds, typical of proton sponges, which can be remarkably short [e.g. N.N 2.714 (3), N-H 1.09 (3), H.N 1.63 (3) Å, N-H.N 169 (3) degrees in (P2)]. Most pyrazoles, however, pack via neutral N-H.N bonds which are formally assisted by resonance (resonance-assisted hydrogen bond, RAHB) through the.N=C-C=C-NH. iminoenamine fragment, contained in the ring, giving rise to dimers, trimers, tetramers and infinite chains of pyrazole molecules. Surprisingly, the resonance does not appear to shorten the N-H.N bond with respect to the accepted mean value N.N 2.97 (10) Å for non-resonant N-H.N bonds. It is shown that this is due to the internal pi-delocalization of the pyrazole ring, which can be hardly increased by the hydrogen-bond interaction, except in symmetrically 3,5-substituted pyrazoles which display N.N distances as short as 2.82 Å, identical C-C and C-N distances in the two halves of the pyrazole molecule, and typical phenomena of N-H.N dynamical proton disorder, detectable by (15)N-CP/MAS solid-state NMR.

Journal Article↗
PubMed2001

Dopamine interaction in the absence and in the presence of Cu2+ ions with macrocyclic and macrobicyclic polyamines containing pyrazole units. Crystal structures of [Cu2(L1)(H2O)2](ClO4)4 and [Cu2(H-1L3)](ClO4)3*2H2O.

The interaction with Cu2+ and dopamine of three polyazacyclophanes containing pyrazole fragments as spacers is described. Formation of mixed complexes Cu2+-macrocycle-dopamine has been studied by potentiometric methods in aqueous solution. The crystal structures of the complexes [Cu2(L1)(H2O)2](ClO4)4*2H2O (4) (L1 = 13,26-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.1(11,14)]octacosa-1(27),11,14(28),24-tetraene) and [Cu2(H-1L3)](HClO4)(ClO4)2*2H2O (6) (L3 = 1,4,7,8,11,14,17,20,21,24,29,32,33,36-tetradecaazapentacyclo[12.12.12.1(6,9).1(19,22).1(31,34)]hentetraconta-6,9(41),19(40),21,31,34(39)-hexaene) are presented. In the first one (4), each Cu2+ coordination site is made up by the three nitrogens of the polyamine bridge, a sp2 pyrazole nitrogen and one water molecule that occupies the axial position of a square pyramid. The distance between the copper ions is 6.788(2) A. In the crystal structure of 6, the coordination geometry around each Cu2+ is square pyramidal with its base being formed by two secondary nitrogens of the bridge and two nitrogen atoms of two different pyrazolate units which act as exobidentate ligands. The axial positions are occupied by the bridgehead nitrogen atoms; the elongation is more pronounced in one of the two sites [Cu(1)-N(1), 2.29(2) A; Cu(2)-N(6), 2.40(1) A]. The Cu-N distances involving the deprotonated pyrazole moieties are significantly shorter than those of the secondary nitrogens. The Cu(1)...Cu(2) distance is 3.960(3) A. The pyrazole in the noncoordinating bridge does not deprotonate and lies to one side of the macrocyclic cavity. One of the aliphatic nitrogens of this bridge is protonated and hydrogen bonded to a water molecule, which is further connected to the sp2 nitrogen of the pyrazole moiety through a hydrogen bond. The solution studies reveal a ready deprotonation of the pyrazole units induced by coordination to Cu2+. In the case of L2 (L2 = 3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.1(11,14)]octacosa-1(27),11,14(28),24-tetraene), deprotonation of both pyrazole subunits is already observed at pH ca. 4 for 2:1 Cu2+:L2 molar ratios. All three free receptors interact with dopamine in aqueous solution. L3 is a receptor particularly interesting with respect to the values of the interaction constants over five logarithmic units at neutral pH, which might suggest an encapsulation of dopamine in the macrocyclic cage. All three receptors form mixed complexes Cu2+-L-dopamine. The affinity for the formation of ternary dopamine complexes is particularly high in the case of the binuclear Cu2+ complexes of the 1-benzyl derivative L1.

Cations, Divalent↗
PubMed1984

(1,3-Dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones. A series of novel central nervous system depressants.

A series of novel (1,3-dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones was synthesized. Pharmacological evaluation of these compounds demonstrated central nervous system depressant activity, potential anticonvulsant properties, and a low order of acute toxicity. In addition, selected compounds showed potential antipsychotic effects. This report focuses on the synthesis and structure-activity relationships of these compounds. (5-Amino-1-ethyl-3-methyl-1H-pyrazol-4-yl)(2-chlorophenyl) methanone (21) was the most active compound against pentylenetetrazole-induced convulsions. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(3-chlorophenyl)methanone (4) also has a favorable anticonvulsant depression ratio. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(3-trifluoromethylphenyl)methan one (8), (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(3-thienyl)methanone (13), and (5-amino-3-ethyl-1-methyl-1H-pyrazol-4-yl)phenylmethanone (14) are very potent depressants. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-thienyl)methanone (12) possessed marked central depressant activity without anticonvulsant activity and without impairment of motor functioning. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl) (2-fluorophenyl)methanone (2) has a behavioral profile suggestive of antipsychotic activity and gave a positive Ames test result.

Animals↗
PubMed1981

Pharmacological and toxicological properties of 4-hydroxypyrazole, a metabolite of pyrazole.

The effects of 4-hydroxypyrazole (4-HP), a principal metabolite of pyrazole, were studied in mice. The compound was toxic, much more so than pyrazole with an LD50 of 1.1 mmol/kg (92 mg/Kg) and doses greater than 1.5 mmol/kg (126 mg/kg) were almost invariably fatal. Toxicity seemed to be centered on the liver with microscopic evidence of centrolobular necrosis apparent. Mouse liver catalase was almost totally inhibited 1 hour after administration of 1 mmol/kg of 4-HP. Tryptophan pyrrolase was also inhibited 4-HP seemed to penetrate into the brain as judged by inhibition of brain catalase activity. A slight increase in brain serotonin concentration was found but 4-HP had no effect in the doses used (1.5 mmol/kg or 4 x 1.0 mmol/kg) in brain or heart noradrenaline. We conclude that the pyrazole-induced decrease in brain noradrenaline is not mediated via 4-HP. Furthermore, simultaneous treatment with methanol and pyrazole, which prevents the formation of 4-HP, did not prevent the decrease in brain noradrenaline levels. Since methanol prevented the pyrazole-induced decrease in brain catalase activity, we can also rule out the possibility that the decrease in brain noradrenaline is secondary to pyrazole-induced inhibition of brain catalase. It is concluded that though 4-HP is an active metabolite of pyrazole, causing, in particular, the hepatotoxicity of the parent molecule, it is not responsible for all the varied biological of pyrazole.

Animals↗
PubMed1994

Synthesis and antiallergic activities of 2-alkyl-3,4-dimethylfuro[2,3-c] pyrazole-5-carboxamides and related compounds.

A series of 2-substituted 3,4-dimethylfuro[2,3-c]pyrazole- 5-carboxamides and related compounds have been synthesized and their antiallergic activities were evaluated. Most derivatives with a lower alkyl group at position 2 were orally active. Among them, N-ethyl-2,3,4-trimethylfuro[2,3-c]pyrazole- 5-carboxamide (III3),2-ethyl-N-methyl-3,4-dimethylfuro[2,3-c]pyrazole-5-ca rboxamide (III14), 2-isopropyl-N-methyl-3,4-dimethylfuro[2,3-c]pyrazole-5- carboxamide (III27),5-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-2,3,4- trimethylfuro [2,3-c]pyrazole (IV1) and 5-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-2-isopropyl-3,4- dimethylfuro[2,3-c]pyrazole (IV3) showed promising antiallergic effects. The structure-activity relation of these 3,4-dimethylfuro[2,3-c] pyrazole derivatives was examined. An amide or 5-oxo-1,3,4-oxadiazole substituent at position 5 was favorable, while introduction of a carboxylic acid or acrylic acid moiety was unfavorable. However, none of these compounds exerted a significant inhibitory effect on mast cell degranulation. Compound III27 and IV3 showed potent anti-allergic activity. We found that they also suppressed histamine-, serotonin-, bradykinin- and substance P-induced ear edema in mice. In compound 48/80-pretreated mice, the preformed mediators in mast cells in the ear were greatly reduced. Under this condition, the bradykinin- and substance P-induced ear edema was suppressed by compound III27 and IV3 to a significantly greater extent than by diphenhydramine combined with methylsergide. These results indicated that the antiallergic effect of 3,4-dimethylfuro[2,3-c]pyrazole derivatives probably involves protection of the vasculature against the effects of challenge by several mediators.

Animals↗
PubMed1987

Production of 4-hydroxypyrazole from the interaction of the alcohol dehydrogenase inhibitor pyrazole with hydroxyl radical.

Pyrazole, an effective inhibitor of alcohol dehydrogenase, was previously shown to be a scavenger of the hydroxyl radical. 4-Hydroxypyrazole is a major metabolite in the urine of animals administered pyrazole in vivo. Experiments were conducted to show that 4-hydroxypyrazole was a product of the interaction of pyrazole with hydroxyl radical generated from three different systems. The systems utilized were the iron-catalyzed oxidation of ascorbate, the coupled oxidation of hypoxanthine by xanthine oxidase, and NADPH-dependent microsomal electron transfer. Ferric-EDTA was added to all the systems to catalyze the production of hydroxyl radicals. A HPLC procedure employing either uv detection or electrochemical detection was utilized to assay for the production of 4-hydroxypyrazole. The three systems all supported the oxidation of pyrazole to 4-hydroxypyrazole by a reaction which was sensitive to inhibition by competitive hydroxyl radical scavengers such as ethanol, mannitol, or dimethyl sulfoxide and to catalase. The sensitivity to catalase implicates H2O2 as the precursor of the hydroxyl radical by all three systems. Superoxide dismutase inhibited production of 4-hydroxypyrazole only in the xanthine oxidase reaction system. In the absence of ferric-EDTA (and azide), microsomes catalyzed the oxidation of pyrazole to 4-hydroxypyrazole by a cytochrome P-450-dependent reaction which was independent of hydroxyl radicals. This latter pathway may be primarily responsible for the in vivo metabolism of pyrazole to 4-hydroxypyrazole. The production of 4-hydroxypyrazole from the interaction of pyrazole with hydroxyl radicals may be a sensitive, rapid technique for the detection of these radicals in certain tissues or under certain conditions, e.g., increasing oxidative stress.

Alcohol Dehydrogenase↗
PubMed1982

Induction of microsomal dimethylnitrosamine demethylase by pyrazole.

Pyrazole, a potent inhibitor of alcohol dehydrogenase, was found to be a potent inducer of the activity of low Km dimethylnitrosamine demethylase (DMN-d). One injection of pyrazole (200 mg/kg body wt) to weanling Wistar rats changed the microsomal DMN demethylase activity by 1.7, 1.9 and 2.5 times the control values at 6, 12 and 24 hr after the injection respectively. Pyrazole administration reduced arylhydrocarbon hydroxylase (AHH) activity. When animals were injected with pyrazole (200 mg/kg body wt) for 1, 2, 3 or 4 consecutive days, the values for DMN-d activity were 277, 297, 306 and 319% of the control values. The corresponding values for AHH were 91, 67, 57 and 45% for 1, 2, 3 and 4 injections respectively. pyrazole-induced DMN-d activity was NADPH dependent and was inhibited by CO; n-butanol gave a 50% inhibition at a concentration of 2 X 10(-3) M. The corresponding value for metyrapone was 1 X 10(-2) M. Cytochrome P-450 was slightly increased by pyrazole and its CO-complex gave an absorption maximum around 451 nm. When the microsomal proteins were separated using sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis, a large increase in a band at about 51,000 daltons was found in the liver microsomes of pyrazole-treated animals.

Animals↗
PubMed1987

Pyrazole as a modifier of liver microsomal monooxygenase in DBA/2N and AKR/J mice.

Effects of pyrazole on liver microsomal monooxygenase was studied in two inbred strains of mice, DBA/2N (D2) and AKR/J (AKR). A selective effect on microsomal monooxygenase was found. In the D2 mouse pyrazole strongly increases the coumarin 7-hydroxylase (CoH) and 7-ethoxycoumarin O-deethylase (ECDE) activities while on the total cytochrome P-450 (P-450) content and ethylmorphine N-demethylase (EMDM) and benzo(a)pyrene hydroxylase (AHH) activities the effect is biphasic (increased with lower doses and decreased with higher). For AKR the effect of pyrazole is different from the D2. The increase of CoH and ECDE is weaker and no biphasic effect for the other three parameters can be seen. Instead only a decrease takes place. The optimal dose of pyrazole for the induction of CoH in the D2 mice is 200 mg/kg once a day during three days. The effect of pyrazole is strongest in animals (D2) of 4-10 weeks old. For young animals (2 weeks old) no effect except of a weak decrease in AHH can be seen. Also for old animals the effect is weak. Recovery of the monooxygenase after pyrazole induction takes place in about 120 hr except for the total P-450 content which is still below normal. No sex dependence in the effect of pyrazole on CoH was found.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1986

Effects of dietary fat on alcohol-pyrazole hepatitis in rats: the pathogenetic role of the nonalcohol dehydrogenase pathway in alcohol-induced hepatic cell injury.

Rats were fed with two different alcohol-containing (36% of total calories) liquid diets of high fat and low fat (35% and 15% of total calories) with or without 2 mM of pyrazole for 12 weeks. At the 12th week, the serum glutamic oxaloacetic transaminase level was significantly elevated in the alcohol-pyrazole high fat group, but not in the low fat group. Ballooning and necrotic changes of the hepatocytes in the centrolobular area were more prominent in the alcohol-pyrazole high fat group than in the low fat group and alcohol alone groups, indicating that high fat diet accelerates the development of alcohol-pyrazole hepatitis. In the alcohol-pyrazole high fat group, a decrease of hepatic microtubules content and an accumulation of hepatic export proteins in the hepatocytes were found. The protein accumulation was prominent only in the ballooned hepatocytes. Hepatic acetaldehyde levels were significantly higher in the alcohol-pyrazole high fat group than in the alcohol-pyrazole low fat group. These results suggest that the accelerated ethanol metabolism in the nonalcohol dehydrogenase pathway by a high fat diet may play an important role in the development of hepatocytic injuries, by impairing the microtubular function of the hepatocytes.

Animals↗
PubMed1977

Evidence for inhibition of dopamine-beta-hydroxylase in vivo after sub-acute pyrazole treatment in rats.

Pyrazole, a widely used inhibitor of alcohol dehydrogenase, has been shown to cause a decrease of brain and heart noradrenaline (NA). An attempt to explain the mechanism of this effect is now described. L-DOPA (50-200 mg/kg, s.c.) was unable to restore brain or heart noradrenaline levels in pyrazole pre-treated rats. After monoamine oxidase inhibition with tranylcypromine or pargyline there was a slight increase in brain NA in these rats but no further increase was observed in response to L-DOPA (30 mg/kg). Brain dopamine levels were relatively higher in pyrazole pre-treated rats. This difference was particularly clear in the hypothalamus but not present at all in striatum. It was impossible to duplicate the above results using nialamide as the monoamine oxidase inhibitor. After depletion of monoamine stores by reserpine (2 x 2 mg/kg) or oxypertine (75 mg/kg) and treatment with tranylcypromine and L-DOPA it is possible to get an indication of the maximal rate of synthesis of NA. In pyrazole treated rats synthesis of NA in brain was 70% reduced and about 50% reduced in heart. Synthesis of dopamine from L-DOPA was unimpaired. Dopamine-beta-hydroxylase activity in the hypothalamus of rats treated for four days with pyrazole (100 mg/kg i.p.) was more than 40% reduced. This inhibition could not be obtained by addition of pyrazole to samples of purified dopamine-beta-hydroxylase. The results strongly suggest that the reason for the decrease in brain and peripheral NA seen after pyrazole administration in rats is due to inhibition of dopamine-beta-hydroxylase.

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