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PubMed1988

Mouse hepatic cytochrome P-450 isozyme induction by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, pyrazole, and phenobarbital.

The effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and pyrazole on mouse hepatic cytochrome P-450 isozyme expression were compared to the P-450 induction pattern elicited by phenobarbital. TCPOBOP and PB administration caused a similar induction profile by increasing microsomal protein and cytochrome P-450 content and the catalytic activities of several monooxygenases in DBA/2N and AKR/J mice. There were, however, several quantitative and some qualitative differences in the induction profile caused by phenobarbital and TCPOBOP. A few strain-related differences were also observed. Immunoblot analysis with polyclonal anti-coumarin hydroxylase (P-450Coh) antibody and epitope-specific monoclonal antibodies 1-7-1 and 2-66-3 showed that both phenobarbital and TCPOBOP increase the amount of P450IIB and P-450Coh. TCPOBOP caused a more pronounced increase in the amount of P-450IIB than phenobarbital, and TCPOBOP also caused an increase in the amount of P-450IA2. These data suggest that in the mouse, TCPOBOP increases mainly the expression of P-450 isozymes responsive to phenobarbital. The effects of pyrazole differed greatly from those caused by TCPOBOP and phenobarbital. In the DBA/2N mice, pyrazole increased coumarin 7-hydroxylation 9.4-fold, whereas in the AKR/J mice the activity was induced only to a level equivalent to the DBA/2N basal level. In immunoblot experiments with anti-P-450Coh antibody, the amount of P-450Coh was considerably higher in DBA/2N mice treated with phenobarbital, TCPOBOP, or pyrazole in comparison with the AKR/J mice, indicating a strain specificity in the inducibility of coumarin 7-hydroxylase by pyrazole.

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↗

PubMed1989

4-(1H-pyrazol-1-yl)-2-butylamine derivatives as inhibitors of blood platelet aggregation.

Reaction of pyrazole and 3,5-dimethylpyrazole with methyl vinyl ketone gave 4-(1H-pyrazol-1-yl)-2-butanones which were converted to N-substituted 4-(1H-pyrazol-1-yl)-2-butylamines by reductive amination using ammonium acetate, primary or secondary amines and sodium cyanoborohydride as reducing agent. These new pyrazole derivatives were found to have an inhibitory effect on platelet aggregation in vitro.

Adenosine Diphosphate↗

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↗

PubMed1990

Non-steroidal antiinflammatory agents, II: Synthesis of novel pyrazole and pyrazoline derivatives of 4(3H)-quinazolinone.

Antiinflammatory and/or analgesic activities have been ascribed to compounds containing the 4(3H)-quinazolinone or pyrazole moiety. Continuation to the previous work in the field of the synthesis of non-steroidal antiinflammatory 4(3H)-quinazolinones, the present investigation deals with the synthesis of new compounds having the pyrazole or pyrazoline and 4(3H)-quinazolinone moieties in one molecule, hoping that such combination might improve their antiinflammatory activity. alpha,beta-unsaturated ketones when treated with hydrazine hydrate achieve cyclization to the corresponding pyrazoline derivatives, whereas, when arylhydrazines are used, pyrazole derivatives are formed.

Animals↗

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↗

PubMed1987

Inhibition of 3(17)beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni by steroidal A ring fused pyrazoles.

Several 2,3- and 3,4-steroidal fused pyrazoles have been investigated as potential inhibitors of NAD(P)H-dependent steroid oxidoreductases. These compounds are proven to be potent, specific inhibitors for 3(17) beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni with Ki values of 6-100 nM. In contrast, the activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans, steroid 5 alpha-reductase from rat prostate, and 3 alpha-hydroxysteroid dehydrogenase from rat liver were unaffected by micromolar concentrations of these compounds. Product and dead-end inhibition studies indicate an ordered association to the beta-dehydrogenase with the cofactor binding prior to substrate or inhibitor. From the results of double inhibition experiments, it is proposed that inhibition occurs through formation of an enzyme-NAD+-inhibitor ternate. On the basis of pH profiles of Vm/Km, Vm, and 1/Ki and of absorbance difference spectra, a hypothetical mechanism of inhibition by the steroidal pyrazoles, drawn by analogy from the inhibition of liver alcohol dehydrogenase by alkylpyrazoles [Theorell, H., & Yonetani, T. (1963) Biochem. Z. 338, 537-553; Andersson, P., Kvassman, J. K., Lindström, A., Oldén, B., & Pettersson, G. (1981) Eur. J. Biochem. 113, 549-554], is reconsidered. The pH studies and enzyme modification experiments by diethyl pyrocarbonate suggest the involvement of histidine in binding of the inhibitor. A modified proposal for the structure of the enzyme-NAD+-steroidal pyrazole complex is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxysteroid Dehydrogenases↗

PubMed1989

A shortened synthesis of 4-(3-aminopropyl) pyrazole, an affinity ligand for alcohol dehydrogenase purification.

The most efficient, specific and rapid procedures for alcohol dehydrogenase (ADH) purification utilize immobilized 4-(3-aminopropyl) pyrazole to which pyrazole sensitive ADHs, i.e. class I isozymes, bind. Because of the length of the reported synthesis of this affinity resin, we synthesized the 4-(3-aminopropyl) pyrazole ligand by a new method in two steps from commercially available nicotinaldehyde. The ligand synthesized by this simplified procedure was directly coupled to the chain-extended support, Activated CH-Sepharose 4B, to yield the same ligand-spacer combination as reported by L.G. Lange and B.L. Vallee (Biochem. 15: 4681-4686, 1976). Human and hamster class I ADHs purified using this resin were homogeneous by SDS-PAGE followed by silver staining. Specific activity and recovery of human class I ADH were comparable to those previously reported.

Alcohol Dehydrogenase↗

PubMed1988

An efficient selection producing structural gene mutants of yeast alcohol dehydrogenase resistant to pyrazole.

Selection for resistance to allyl alcohol in respiration-incompetent Saccharomyces cerevisiae produces a high proportion of mutants that can be localized within the ADH2 structural gene and that still, because of the type of selection employed, retain enzyme activity. We show here that a similar type of selection produces a similarly high proportion of mutants resistant to the competitive inhibitor pyrazole. The first four mutants examined, picked at random from a collection of spontaneous pyrazole-resistant mutants, show altered--usually increased--KM values for ethanol and NAD+, and markedly increased K1 values for pyrazole, compared with the wild type. When these kinetic measures and their electrophoretic mobilities were compared, all the mutants could be clearly distinguished from each other as well as from wild type. Genetic analysis shows these mutants to be close to and probably resident in the structural gene. For a variety of reasons, these mutants are even more favorable subjects for population genetic analysis and the dissection of molecular microevolution than are allyl alcohol-resistant mutants.

Alcohol Dehydrogenase↗