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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↗

PubMed1988

Amidinosemicarbazido derivatives of pyrazole: synthesis and inhibitory effect on blood coagulation and platelet aggregation.

Amidinosemicarbazido derivatives of pyrazole having various substituents on pyrazole ring were prepared and their effect on platelet function and blood coagulation was determined in vitro. Platelet aggregation and serotonin release induced by ADP, collagen, arachidonic acid and thrombin were markedly inhibited by pyrazole derivatives at mM concentrations. Compounds with a hydrophobic nucleus at position 1 of the pyrazole ring showed the most potent antiplatelet activity. On the contrary, their effect on blood coagulation was faintly inhibitory.

Anticoagulants↗

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

An investigation of the metabolism of N-nitroso-N-methylaniline by phenobarbital- and pyrazole-induced Sprague-Dawley rat liver and esophagus derived S-9.

The metabolism and mutagenicity of the esophageal carcinogen N-nitroso-N-methylaniline (NMA) was studied using hepatic and esophageal 9000 X g supernatant (S-9) preparations from Sprague-Dawley rats induced with pyrazole and phenobarbital. Only pyrazole-induced hepatic S-9 was able to dose-dependently activate NMA to a mutagen in the Ames assay and specifically in Salmonella typhimurium TA1537. NMA in the presence of phenobarbital-induced S-9 gave a very weak non-dose dependent mutagenic response. Metabolism of NMA by the two induced hepatic and esophageal S-9 fractions yielded aniline and N-methylaniline (MA). Phenobarbital-induced S-9 from both tissues also afforded phenol, while none was found with the pyrazole-induced preparations. Phenol formation presumably arose from the direct oxidative demethylation of NMA via a benzenediazonium ion (BDI) intermediate. The results indicate that an important metabolic pathway for NMA, with both inducing agents, entails an initial denitrosation to yield MA, which in turn rapidly undergoes oxidative demethylation to aniline. The conversion of NMA to phenol also suggests that direct demethylation of NMA in the phenobarbital-induced system is an important metabolic pathway.

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↗

PubMed1987

Interaction of dopamine beta-mono-oxygenase with substituted imidazoles and pyrazoles. Catalysis and inhibition.

The interaction of dopamine beta-mono-oxygenase (DBM) with substrate analogues possessing either imidazole or pyrazole functionalities at the alkyl chain terminus was investigated. 1-(4-Hydroxybenzyl)imidazole (4-HOBI) is an active substrate for DBM, and it exhibits the expected ascorbate- and fumarate-dependencies and normal kinetic behaviour at concentrations up to 10 mM. 4-Hydroxybenzaldehyde was identified as the product formed from 4-HOBI on the basis of h.p.l.c. and g.c.-m.s. analysis, and its formation exhibits the expected 1:1 stoichiometry with O2 consumption. The 4-HOBI/DBM reaction is kinetically comparable with other DBM activities, and 4-HOBI is the first substrate analogue yet reported that exhibits substantial activity though lacking a terminal amino group. Introduction of a methyl substituent at the 2-position of the imidazole ring abolishes substrate activity, probably through a steric effect. 1-(4-Hydroxybenzyl)pyrazole, where imidazole is replaced by the isomeric pyrazole moiety, is a potent DBM inhibitor, and not a substrate. These results represent the first report of an active heterocyclic substrate or inhibitor for this enzyme, and establish the basis for the design of new classes of DBM substrates and inhibitors.

Catalysis↗

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

The effect of pyrazole, phenobarbital, ethanol and 3-methylcholanthrene pretreatment on the in vivo and in vitro genotoxicity of N-nitrosopyrrolidine.

The in vitro genotoxicity of N-nitrosopyrrolidine (NPy) has been studied in Salmonella typhimurium strain TA1535 in the presence of untreated and pyrazole-, phenobarbital (PB)-, 4-day ethanol (EtOH)-, 10-day EtOH- and 3-methylcholanthrene (3-MC)-pretreated male Sprague-Dawley rat liver S-9 fractions. Unless stated otherwise, the last pretreatment exposure was 24 h prior to sacrifice and isolation of hepatic enzymes. Pyrazole and EtOH (10-day exposure) both effectively induced the conversion of NPy into a mutagen at doses as low as 500 microM. PB and EtOH (4-day exposure) had a modest enhancing effect on the number of revertants scored, while 3-MC and uninduced S-9 fractions gave results not significantly different from background (no NPy). The same pretreatment protocols were used to determine the in vivo genotoxicity of NPy in rat liver using the technique of alkaline elution. The inducing agents had the exact opposite effect in vivo with control, 3-MC- and 4-day EtOH-treated animals showing the highest level of DNA damage. Pyrazole and 10-day EtOH pretreatments gave DNA elution rate constants comparable to animals not treated with NPy. However, in 10-day EtOH-pretreated animals which were administered NPy without a 24-h interval between EtOH and NPy exposure, DNA damage was observed at the same high levels as was seen in uninduced and 3-MC treated rats. The results are discussed in terms of a detoxification role for microsomal proteins and that the observed in vivo DNA damage may be induced by enzymes associated with the nuclear compartment.

Animals↗

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↗

PubMed1988

Purification and characterization of a liver microsomal cytochrome P-450 isoenzyme with a high affinity and metabolic capacity for coumarin from pyrazole-treated D2 mice.

Microsomal coumarin 7-hydroxylase activity is regulated differently from several other monooxygenase enzymes, at least in mice [Wood, A. W. and Conney, A. H. (1974) Science (Wash. DC) 612-614]. Recently we found that in D2 mice this activity is strongly and selectivity induced by pyrazole [Juvonen, R. O., Kaipainen, P. K. and Lang, M. A. (1985) Eur. J. Biochem. 152-3-8]. This paper describes the purification of the pyrazole-inducible cytochrome P-450 isoenzyme. Because of the lability of the protein, a special procedure for the purification was developed. The procedure is based on a combination of hydrophobic and ion-exchange chromatography and the presence of 100 microM coumarin in the preparations throughout the whole purification. Coumarin effectively protected the P-450 from degradation and also converted the pyrazole-inducible P-450 to its high-spin state. This enabled us to choose only those fractions for further purification where the P-450(s) was in its high-spin state (rather than measuring the content of the total P-450). As a result the purified protein had an apparent molecular mass of 49.7 kDa, a specific content of 19.9 nmol/mg protein and a very high affinity and metabolic capacity for coumarin.

Animals↗