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PubMed1977

Effects of pyrazole treatment of physical status and brain biogenic amines in rats.

The recovery of brain noradrenaline (NA) from a single dose of 100 mg/kg pyrazole was rapid, but after 500 mg/kg brain NA levels were still maximally reduced 3 days later and did not return to normal until 7 days after injection. The consumption of water followed a similar time course at this dose. Sub-acute experiments were carried out in two sets of animals: those with free access to food and water throughout the experiment and those which during the latter half of the experiment received a known, restricted quantity of food and fluid by gastric intubation. Diet restriction did not alter the pyrazole induced decrease in brain NA and potentiated the decrease observed in the heart. A significant increase in brain 5-hydroxyindoleacetic acid was observed with pyrazole 100 mg/kg in both diet schedules. In addition to the disturbances in food and water consumption, pyrazole also caused a decrease in locomotor activity which was only partly due to the starvation. Rectal temperature did not change. At the higher pyrazole dose in the rats fed by intubation there was incomplete emptying of the stomach. It is concluded that these many changes demonstrate the non-specificity of pyrazole and caution is advocated in its use combined with ethanol in research on experimental alcoholism.

Animals↗

PubMed1992

Time course characterization of the induction of cytochrome P-450 2E1 by pyrazole and 4-methylpyrazole.

Cytochrome P-450 (P-450) 2E1 is under transcriptional and post-transcriptional control. Well-defined time courses were carried out to compare the effect of pyrazole and 4-methylpyrazole on catalytic activities, apo-P-450 2E1 levels and mRNA levels to evaluate whether induction of P-450 2E1 is preceded by altered mRNA levels. Two days of treatment with pyrazole or three days of treatment with 4-methylpyrazole resulted in significant induction of P-450 2E1, as assessed by Western blots and by oxidation of dimethylnitrosamine or p-nitrophenol. No changes in mRNA levels were detected with either inducer. Within 2 h of the second treatment with pyrazole, maximal induction of P-450 2E1 was observed, however, a 8-12 h time-dependent period was required after the third treatment with 4-methylpyrazole for maximal induction. Irrespective of the time period, increased catalytic activity and P-450 2E1 appears to reflect a post-transcriptional mechanism. A single treatment with 4-methylpyrazole increased P-450 2B1/B2 levels and oxidation of pentoxyresorufin about 2- to 3-fold. No change in mRNA levels for 2B1/B2 was observed. Although significant, the induction of 2B1/B2 by 4-methylpyrazole is more than an order of magnitude less than that by phenobarbital. Pyrazole did not induce 2B1/B2. It appears that, similar to acetone and ethanol, 4-methylpyrazole may increase several P-450 isozymes, whereas pyrazole is more specific for induction of P-450 2E1.

Animals↗

PubMed1991

Posttranscriptional regulation of coumarin 7-hydroxylase induction by xenobiotics in mouse liver: mRNA stabilization by pyrazole.

The induction mechanism by pyrazole or phenobarbital of coumarin 7-hydroxylase (cytochrome P450coh) was investigated in DBA/2J male mice. The P450coh mRNA in the pyrazole-induced mice was increased gradually to a 20-fold higher level within 48 h, yet transcription of the P450coh gene was not affected. The half-life of P450coh mRNA, on the other hand, was at least 4-fold longer in the pyrazole-induced DBA/2J (approximately 6.0 h) than in control DBA/2J (approximately 1.5 h) male mice. The stabilization of P450coh mRNA, therefore, is the primary mechanism for the induction by pyrazole of coumarin 7-hydroxylase. Phenobarbital, on the other hand, regulates the induction either translationally or posttranslationally. This drug affected neither the P450coh mRNA nor the P450coh gene's transcription levels in the DBA/2J male mice, although Western blots showed approximately a 3-fold increase of the P450coh protein in the liver microsomes of the drug-treated mice. The results indicate, therefore, that both phenobarbital and pyrazole regulate the P450coh induction posttranscriptionally; the former inducer enhances the translational efficiency of P450coh mRNA or alters the degradation rate of P450coh aproprotein, while the latter stabilizes P450coh mRNA.

Animals↗

PubMed1979

3-Substituted pyrazole derivatives as inhibitors and inactivators of liver alcohol dehydrogenase.

3-Substituted pyrazoles, HOCH2 (1), HOCH2CH2 (2), HOCH2CH2CH2 (3), ClCH2 (4), ClCH2CH2 (5), ClCH2CH2CH2 (6), and CH3CO (7), were synthesized and evaluated in vitro on horse liver alcohol dehydrogenase for their potential as inhibitors of ethanol metabolism. 1 to 6 bound to the enzyme-NAD+ complex with dissociation constants of 40 to 200 microM, much higher than the constants for the corresponding 4-substituted pyrazoles, but with the same absorption maximum at 295 nm. 4 inactivated the enzyme within a few minutes, but NAD+ protected against reaction, and 4 nonspecifically alkylated many sulfur atoms in the protein. The isomer, 4-(chloromethyl)pyrazole, behaved similarly, 5 and 6 strongly inhibited the enzyme in the presence of NAD+, due to formation of the slowly dissociable (10(-3)s-1) enzyme-NAD+-pyrazole complex, but did not irreversibly inactivate the enzyme. 7 inhibits the enzyme weakly (Kp = 5 mM). It appears that the 3-substituted pyrazoles bind to the enzyme-NAD+ complex with the reactive functional group improperly positioned for specific irreversible reaction.

Alcohol Oxidoreductases↗

PubMed1977

Effects of pyrazole and 3-amino-1,2,4-triazole on the metabolism and toxicity of dimethylnitrosamine in the rat.

Pretreatment of rats with pyrazole or 3-amino-1,2,4-triazole (3-AT) known inhibitors of alcohol metabolism, profoundly inhibited the metabolism of dimethylnitrosamine (DMN), both in terms of [14C]CO2 excretion and of the decline in the blood concentration. Additionally, 4-methylpyrazole, tetraethylthiuram disulfide (disulfiram), methanol, and ethanol inhibited the metabolism of DMN in the whole animal. In parallel experiments with [14C]aminopyrine, no substantial inhibitory effect was found with pyrazole, 3-AT, or disulfiram pretreatment. Investigations into the effects of pyrazole and 3-AT pretreatment on the acute toxicity and hepatotoxicity of DMN showed that pyrazole significantly increased the median lethal dose (LD50) of DMN and provided substantial protection against the hepatotoxicity of DMN, in that centriblobular necrosis was not seen at dose levels of DMN up to 25 mg/kg and early histochemical changes indicative of liver injury were not observed at a dose level of 15 mg DMN/kg. In contrast, 3-AT pretreatment did not affect the LD50 of DMN or provide any protection against the hepatotoxicity of DMN. Further, although both inhibitors delayed the incorporation of radioactivity from [14C]DMN into hepatic subcellular organelles, pyrazole was significantly more effective than was 3-AT.

Amitrole↗

PubMed1978

Inhibition of dopamine beta-hydroxylase by 4-hydroxypyrazole: ethanol-pyrazole effects on serum dopamine beta-hydroxylase in vivo.

Chronic pyrazole treatment caused a 40% decrease in rat serum dopamine beta-hydroxylase (DBH) activity. Ethanol given simultaneously with pyrazole prevented the inhibition. 4-Hydroxypyrazole, the major metabolite of pyrazole, competitively inhibited both rat serum DBH and partially purified bovine adrenal DBH in vitro. In vivo, 4-hydroxypyrazole caused large decreases in rat serum (53-84%) and adrenal (97%) DBH activity but had no effect on brain enzyme. The decrease in rat serum DBH after chronic pyrazole treatment and the pyrazole-induced changes in physiological parameters, such as body weight and temperature, may be due to the formation of 4-hydroxypyrazole.

Adrenal Glands↗

PubMed1991

Increased catalytic activity of cytochrome P-450IIE1 in pericentral hepatocytes compared to periportal hepatocytes isolated from pyrazole-treated rats.

Cytochrome P-450IIE1 is induced by a variety of agents, including acetone, ethanol and pyrazole. Recent studies employing immunohistochemical methods have shown that P-450IIE1 was expressed primarily in the pericentral zone of the liver. In order to evaluate whether catalytic activity of P-450IIE1 is preferentially localized in the pericentral zone of the liver acinus, the oxidation of aniline and p-nitrophenol, two effective substrates for P-450IIE1, by periportal and pericentral hepatocytes isolated from pyrazole-treated rats was determined. Periportal and pericentral hepatocytes were prepared by a digitonin-collagenase procedure; the marker enzymes glutamine synthetase and gamma-glutamyl transpeptidase indicated reasonable separation of the two cell populations. Viability, yield and total cytochrome P-450 content were similar for the periportal and pericentral hepatocytes. Pericentral hepatocytes oxidized aniline and p-nitrophenol at rates that were 2-4-fold greater than periportal hepatocytes under a variety of conditions. Carbon monoxide inhibited the oxidation of the substrates with both preparations and abolished the increased oxidation found with the pericentral hepatocytes. Pyrazole or 4-methylpyrazole, added in vitro, effectively inhibited the oxidation of aniline and p-nitrophenol and prevented the augmented rate of oxidation by the pericentral hepatocytes. Western blots carried out using isolated microsomes revealed a more than 2-fold increase in immunochemical staining with microsomes isolated from the pericentral hepatocytes, which correlated to the 2-4-fold increase in the rate of oxidation of aniline or p-nitrophenol by the pericentral hepatocytes. These results suggest that functional catalytic activity of cytochrome P-450IIE1 is preferentially localized in the pericentral zone of the liver acinus, and that most of the induction by pyrazole of P-450IIE1 appears to occur within the pericentral zone.

Aniline Compounds↗

PubMed1992

Effect of pyrazole, cobalt and phenobarbital on mouse liver cytochrome P-450 2a-4/5 (Cyp2a-4/5) expression.

Pyrazole, cobalt and phenobarbital increase the activity of coumarin 7-hydroxylase (COH) in mouse liver. To study the mechanism of this increase, we measured the expression of the cytochrome P-450 2a-4/5 (Cyp2a-4/5) complex, which mediates testosterone 15 alpha-hydroxylase and COH activities, as a function of dose and time after the treatment of C57BL/6 (B6) and DBA/2 (D2) male mice with the inducers. COH activity and Cyp2a-4/5 steady-state mRNA levels were increased in both strains in response to the inducers. No marked effect occurred with testosterone 15 alpha-hydroxylase or activities associated with Cyp1a-1 or Cyp2e-1. A 2-7-fold increase in response to the inducers was seen in the amount of P-450Coh (cytochrome P-450 isoenzyme catalysing coumarin 7-hydroxylation) protein in Western immunoblots. PCR amplification of a 1 kb region in Cyp2a-4/5-mRNA-derived cDNA, followed by cutting at the diagnostic PstI site, showed that most of the steady-state mRNA consisted of Cyp2a-5, which is also the form most affected by pyrazole. Nuclear run-off analysis revealed no increase in the transcription rate of Cyp2a-4/5 after pyrazole or cobalt treatment, whereas a 2-3-fold increase occurred after phenobarbital pretreatment in B6 mice. Together with previous reports [Aida & Negishi (1991) Biochemistry 30, 8041-8045], the current data suggest that both pyrazole and cobalt increase COH catalytic activity by affecting Cyp2a-5 by post-transcriptional mechanisms in mice.

Animals↗

PubMed1992

Synthesis and antiplatelet activities of N-arylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives.

A series of new 1- and 2-arylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives were synthesized and examined for their antiplatelet activities. Some of these compounds showed significant inhibitory activities. Among them, 1-phenylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6(1H)-one (4a), 2-(2'-methoxyphenyl)methyl-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H)- one (3e) and 2-(3'-methoxyphenyl)methyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-(2H) - one (3f) were the most effective. These inhibitors acted in a concentration-dependent manner. The antiplatelet effect of compound 3f is due to the inhibition of thromboxane A2 formation and the blockade of thromboxane A2/prostaglandin endoperoxide receptor in washed rabbit platelets.

Animals↗

PubMedDate not supplied

[A comparative study of the effect of pyrazole on the activity of enzymes in the alcohol/polyol dehydrogenase family].

A comparative study of the effect of pyrazol, an inhibitor of the coenzyme-binding site of alcohol dehydrogenases, on the activity of enzymes of the alcohol/polyol dehydrogenase group has been carried out. Commercial preparations of alcohol dehydrogenases from the cytoplasm of horse liver cells and yeast cells, as well as the enzyme from the cytoplasm of Trichosporon pullulans cells was completely inhibited by 1 mM pyrazol, while alcohol dehydrogenases from Candida utilis and Saccharomyces carlsbergensis were inhibited only by 25% and the enzymes from Saccharomyces cerevisiae and Torulopsis candida by 30 and 38%, respectively. The inhibition degree of alcohol dehydrogenases from the cytoplasm of liver cells of various mammals (bull, calf, rat, gopher) and birds (hen, pheasant, duck) varied from 12 to 42% in the presence of 1 mM pyrazol. The activity of sorbitol dehydrogenase from the liver cytoplasm of these mammals and birds changed neither in the presence of 1 mM pyrazol, nor in the case of a 15-fold increase of the inhibitor concentration. Possible structural differences in the coenzyme-binding site of the active center of the enzymes under study are discussed.

Alcohol Dehydrogenase↗

PubMed1978

Combined action of pyrazole and ethanol on a rat liver: histochemical and ultrastructural study.

The effect on a rat liver of combined administration of pyrazole and ethanol was studied histochemically and by electron microscopy. The study revealed strong hepatotoxic action of pyrazole combined with ethanol. Feeding with ethanol alone induces slight alterations in the liver, pyrazole alone affects the liver but slightly, whereas a combined administration of pyrazole and ethanol both by light and electron microscopy examination revealed a strong toxic action leading to severe damage of the liver cells including necrosis.

Acid Phosphatase↗

PubMed1978

Heterocyclic tricycles as potential CNS agents I: 4-aminoalkylindeno[1,2-c]pyrazoles.

Series of 4-(3-dimethylaminopropyl)-4-hydroxyindeno[1,2-c]pyrazoles and 4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c-]pyrazoles were synthesized and identified. The compounds were evaluated as potential CNS agents using spontaneous and forced motor activity in mice as an initial test. 2-Ethyl-3-methyl-4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c]pyrazole possessed significant biological activity.

Animals↗

PubMed1992

Synthesis and anti-inflammatory activity of fluorinated phenyl styryl ketones and N-phenyl-5-substituted aryl-3-p-(fluorophenyl) pyrazolins and pyrazoles.

Various N-phenyl-5-substituted aryl-3-p-(fluorophenyl) pyrazolins and pyrazoles were synthesized by cyclization of the corresponding 4-(fluorophenyl) styryl and 4-(fluorophenyl) dibromostyryl ketones. These compounds were characterized by elemental analysis and UV, infrared, and nuclear magnetic spectral data. All substituted p-(fluorophenyl) styryl ketones [250 mg/kg orally (po)] possessed anti-inflammatory activity, as reflected by their ability to provide protection (51-70%) against carrageenin-induced edema in rat paw. Indomethacin (10 mg/kg, po) and dehydrozingerone (70 mg/kg, po), used as standard reference drugs, provided 97 and 60% protection, respectively. All compounds (0.20 mM) showed ability to denature bovine serum albumin, as observed in in vitro inhibition studies. Inhibition ranged from 7 to 59% for substituted p-(fluorophenyl) styryl ketones and from 12 to 21% for pyrazoles. No correlation was found between the anti-inflammatory activity of p-(fluorophenyl) styryl ketones or substituted pyrazoles and their effectiveness at inhibiting bovine serum albumin denaturation. The low toxicity of p-(fluorophenyl) styryl ketones was reflected by the dose that was lethal in 50% of the cases tested (2000-2500 mg/kg).

Animals↗

PubMed1992

Differences in hepatic microsomal cytochrome P-450 isoenzyme induction by pyrazole, chronic ethanol, 3-methylcholanthrene, and phenobarbital in high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS) rats.

High and low alcohol sensitivity (HAS and LAS) rats have been selected for their differences in ethanol-induced sleep time. Liver monooxygenase activities were studied in HAS and LAS rats before and after treatments with known inducers such as chronic ethanol, pyrazole, 3-methylcholanthrene (3-MC) and phenobarbital (PB) to determine whether the selection procedure also selected for differences in the cytochrome P-450 (P-450) inducibility. This previously has been shown with long sleep (LS) and short sleep (SS) mice, which were selected using a similar criterion. 3-MC and PB, in conjunction with chronic ethanol treatment, were used in order to evaluate the interactions of ethanol with these inducers. Prior to treatment, total P-450 content was slightly lower in LAS than in HAS rats. However, both lines displayed the same microsomal monooxygenase activities related to different P-450 isozymes. This was demonstrated by ethoxyresorufin deethylation (EROD) for cytochrome P-450 1A1 (CYP1A1), acetanilide hydroxylation (ACET) for CYP1A2, pentoxyresorufin dealkylation (PROD) for CYP2B, 1-butanol oxidation (BUTAN) and N-nitrosodimethylamine demethylation (NDMA) for CYP2E1. After the different treatments, HAS rats did not differ from LAS rats in their CYP2E1 inducibility. However, pyrazole, PB and 3-MC treatment led to differences in CYP1A and CYP2B monooxygenase activities between the two lines. The enhancement of PROD by pyrazole treatment was less prominent in LAS (1.7-fold of the control value) than in HAS rats (3.8-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗

PubMed1978

Pyrazole-induced thyroid necrosis: a distinct organ lesion.

One oral dose of pyrazole caused necrosis of rat thyroid follicular epithelial cells but spared the parafollicular (C) cells and the parathyroid glands. Serum thyroxine (T4) and triiodothyronine (T3) were significantly decreased on day 3 after pyrazole administration and were immeasurable on day 5. At day 5 the thyroid was enlarged and the concentration of thyroid-stimulating hormone in the serum was increased, indicating an appropriate pituitary response to a primary lesion in the thyroid. Doses of pyrazole which produced no morphologic change in the thyroids also significantly depressed the concentrations of T4 and T3 in the serum.

Animals↗

PubMed1975

Effect of pyrazole on ethanol metabolism in ethanol-tolerant rats.

Adult male rats were pair-fed liquid diets, providing 37% of calories as ethanol or sucrose, for 1 month. Alcohol dehydrogenase (ADH) activity in the cytosol fractions of liver homogenates from the two groups did not differ with respect to total activity per 100 g body weight, Km for ethanol, or Ki for pyrazole. Other rats, fed in the same way, were fasted for 18-24 H, then given an intraperitoneal injection of pyrazole followed 1 h later by an injection of ethanol, 3g/kg. Blood alcohol curves showed an unexplained slower rise to maximum level in the chronic alcohol group. Both groups showed a period of several hours in which the blood alcohol stayed at the respective maximum concentrations, which were higher in the control group. After 7-8h the alcohol concentration began to fall in both groups, significantly more rapidly in the chronic alcohol-fed animals. A kinetic analysis shows that the results are adequately explained by the known effects of pyrazole on the ADH-mitochondrial system. The results are interpreted as evidence against the function of any microsomal ethanol oxidizing system in vivo.

Alcohol Oxidoreductases↗

PubMedDate not supplied

1H and 13C NMR study of proton transfer in azoles. Mechanism of proton transfer in pyrazole in solutions containing bis-(acetylacetonato) nickel (II).

Proton transfer in pyrazole systems involving interaction with a paramagnetic transition metal complex has been studied with 1H and 13C NMR techniques. Kinetics of the ligand exchange in the pyrazole complex of bis-(acetylacetonato)nickel (II) has been investigated, and hyperfine coupling constants for the interaction of the nickel unpaired electron with the ligand nuclei in the complex have been determined. Catalytic admixtures of bis-(acetylacetonato)nickel (II) are shown to modify the mechanism of the proton transfer in pyrazole. The spectral data are discussed in terms of outer-sphere coordination and cooperative proton transfer effects.

Chemical Phenomena↗

PubMed1976

Influence of pyrazole on hepatic [1-14C] palmitate oxidation during acute ethanol intoxication.

When studied at different times following ethanol intubation, the effects of pyrazole, administered to rats prior to ethanol, affects differently the alcohol-induced disturbances in hepatic [1-14C] palmitate oxidation. This peculiar time-course of the pyrazole induced effects supports the relationship between active ethanol oxidation and inhibition of hepatic fatty acid oxidation, but also emphasizes the caution which must be taken when using pyrazole to study "in vivo" the mechanisms involved in the alcohol induced fatty liver.

Alcoholic Intoxication↗