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PubMed1987

Increased sensitivity of the microsomal oxidation of ethanol to inhibition by pyrazole and 4-methylpyrazole after chronic ethanol treatment.

Pyrazole and 4-methylpyrazole, inhibitors of the oxidation of ethanol by alcohol dehydrogenase, also inhibit microsomal metabolism of ethanol. The inhibitory effectiveness of these agents was increased in microsomes isolated from rats treated chronically with ethanol as compared to microsomes from pair-fed controls or from rats treated with other cytochrome P-450 inducers such as phenobarbital or 3-methylcholanthrene. Pyrazole and 4-methylpyrazole produced type II binding spectra with all the microsomal preparations. However, there was an increased affinity (lower Ks value) for these agents by the microsomes from the ethanol-fed rats. A correlation between Ks values and inhibitory effectiveness against ethanol oxidation by the various microsomal preparations could be observed. This suggests that an increase in affinity, which may reflect the induction of an alcohol-preferring isozyme of cytochrome P-450, is responsible for the increased inhibitory effectiveness of pyrazole and 4-methylpyrazole towards ethanol oxidation by microsomes after chronic ethanol treatment. One difference between pyrazole and 4-methylpyrazole was the increased affinity and inhibitory effectiveness of the latter but not the former with microsomes from rats treated with 3-methylcholanthrene. This could be due to the ability of 4-methylpyrazole, compared to pyrazole, to interact with and induce several isozymes of cytochrome P-450. Pyrazole and 4-methylpyrazole are often utilized to evaluate ethanol metabolism by alcohol-dehydrogenase-dependent and -independent pathways. However, the sensitivity of microsomal ethanol oxidation to inhibition by these agents, especially after chronic ethanol treatment, would suggest that their use in this regard is complex and could tend to underestimate the contribution of the microsomal pathway towards the metabolic tolerance found after ethanol treatment.

Animals↗

PubMed1991

Inducibility of P450Coh by pyrazole and its derivatives.

Pyrazole and several of its derivatives increase the hepatic microsomal coumarin 7-hydroxylase to a variable extent. The strongest inducers are pyrazole itself and those derivatives which have a hydroxy group or a halogen at the 4-position of the molecule. The increase in coumarin 7-hydroxylase is due to an increase in the microsomal P450Coh and the corresponding mRNA. The increase of P450Coh by pyrazole and 4-hydroxypyrazole is selective because several other mono-oxygenase enzymes and the total P450 content are either not affected or even decreased. These include the testosterone 15 alpha-hydroxylase (P45015 alpha), a close structural analogue of P450Coh, which is induced only marginally by pyrazole and even decreased by 4-iodopyrazole, and P450ac which is decreased by pyrazole and 4-hydroxypyrazole. Introducing a methyl residue at the 4-position will alter the induction properties of the compound essentially bymaking it less selective for P450Coh. These results demonstrate the special selective action of pyrazole and some of its derivatives on the hepatic microsomal mono-oxygenase complex and the unique mode of regulation of the cytochrome P450Coh even within the same subfamily of cytochromes P450.

Animals↗

PubMed1979

Ethanol, disulfiram, and pyrazole: effects on interferon production in mice.

The effects of ethanol alone or combined with pyrazole or disulfiram were studied in reference to interferon production. Saline, ethanol (2 g/kg), pyrazole (2 mg/kg), or disulfiram (2 mg/kg) were injected, intraperitoneally, 3 hr after poly I:C, an interferon inducer. Drugs were administered either by a single injection, or twice daily for 7 days, and the mice were sacrificed 6 hr after poly I:C. Sera from mice were pooled, dialyzed, and assayed for interferon by the microplaque reduction method. Administration of ethanol alone reduced interferon production 76% and 66% after the single and the multiple injections, respectively. A similar inhibition of interferon occurred after either pyrazole or disulfiram, with a greater potency for pyrazole. Treatment with pyrazole prior to ethanol reduced interferon production further, but only after the 7-day schedule. All drugs tested affected cellular immunity as measured by interferon production. Moreover, reduced interferon production by these agents was associated with a loss of splenic lymphoid tissue, suggesting that ethanol, pyrazole, and disulfiram could affect susceptibility to viral infection.

Animals↗

PubMedDate not supplied

Inhibition of carcinogenicities of 1,2-dimethylhydrazine and azoxymethane by pyrazole.

Inhibitory effects of pyrazole on the carcinogenicities of 2 large-bowel carcinogens, 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM), were examined, because our previous study revealed that pyrazole completely inhibited the induction of mutations by these carcinogens in the host-mediated mutation assay. ICR male mice were treated subcutaneously once a week for 20 weeks either with DMH or with AOM. Pyrazole was given orally to mice 2 h before treatment with the carcinogen. Pathological examinations were conducted 36 weeks after the first treatment. Treatment with DMH or AOM alone induced colorectal and/or anal tumorigenic lesions in 92% (23/25) mice of the DMH group and 100% (22/22) mice of the AOM group. By contrast, none of the animals in the combined treatment groups (carcinogen + pyrazole) developed those tumors. On the other hand, 50% (13/26) of mice treated with DMH alone and 78% (18/23) of mice treated with AOM alone developed vascular tumors. Pretreatment of mice with pyrazole reduced the percentage of mice bearing this type of tumor to about 30% of that in the carcinogen group with either carcinogen. These results clearly show that pyrazole has the ability to inhibit carcinogenicities of DMH and AOM, especially for the colorectum and anus, and indicate that the inhibition studies of mutation induction in vivo provide a useful tool for the screening for inhibitors of the carcinogenicities of DMH and AOM.

1,2-Dimethylhydrazine↗

PubMed1979

Histochemical and morphological evaluation of cerebral cortex of newborn rat in the course of joint ethanol and pyrazole administration.

The object of the study was the cerebral cortex of newborn rat. Tissue material was collected from the 2-nd to the 8-th hour after birth both from control animals and newborns whose mothers had been given both ethanol and pyrazole throughout gestation period, and also either ethanol alone or pyrazole. The drug were administered by gastric tube, in doses: ethanol 8.0 g/kg body weight, pyrazole 36 mg/kg body weight. Histochemical studies revealed variation in the intensity of reaction of the respiratory enzymes during examination of the cortex of newborns whose mothers had been fed with ethanol alone, or pyrazole alone. A strong inhibition of enzymatic reaction was observed in the examined cerebral cortex of newborns after a joint ethanol and pyrazole administration. Morphological studies showed an inhibition of maturing process of the cerebral cortex cells of animals treated with ethanol alone, whereas the cerebral cortex of animals whose mothers had been given both ethanol and pyrazole, presented symptoms allowing to diagnose encephalitis congenita symptomatica.

Animals↗

PubMed2003

Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression.

Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.

Alanine Transaminase↗

PubMed1982

Pyrazole binding in crystalline binary and ternary complexes with liver alcohol dehydrogenase.

Pyrazole is a strong inhibitor of liver alcohol dehydrogenase in combination with oxidized coenzyme NAD+. We have studied three different complexes of the inhibitor with the enzyme by using crystallographic methods: (1) the binary complex with pyrazole to 3.2-A resolution, (2) the ternary ternary complex with NAD+-4-iodopyrazole to 2.9-A resolution. Crystals of the binary complex are isomorphous to the apoenzyme, and pyrazole binds to the active-site zinc atom in a way analogous to imidazole. Crystals of the two ternary complexes are isomorphous with the ternary alcohol dehydrogenase-NADH-dimethyl sulfoxide complex. One of the nitrogen atoms of the pyrazole ring is directly bound to the active-site zinc atom with a Zn-N bond distance of 2.1A. The other nitrogen atom is 2 A from the C4 atom of the nicotinamide ring of the coenzyme. The iodine atom in 4-iodopyrazole is located in the hydrophobic substrate cleft. The effect of substitutions on the pyrazole ring are discussed in relation to the structure of the active site and substrate pocket. Pyrazole derivatives with long alkyl chains bound in the 4 position are outstanding inhibitors, and this property is related to the topography of the hydrophobic substrate cleft. The conformation of the oxidized coenzyme in the ternary complexes is essentially the same as that of the reduced coenzyme NADH in the NADH-dimethyl sulfoxide complex.

Alcohol Dehydrogenase↗

PubMed2000

Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists.

We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ERalpha than on the ERbeta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERalpha-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERalpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERalpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERalpha. It also activates gene transcription only through ERalpha. Thus, this compound represents the first ERalpha-specific agonist. We investigated the molecular basis for the exceptional ERalpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ERalpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERalpha has a smaller residue than ERbeta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERalpha.

Binding, Competitive↗

PubMed1979

Alkylating nucleosides. 2. Synthesis and cytostatic activity of bromomethylpyrazole and pyrazole nitrogen mustard nucleosides.

Glycosylation of ethyl 3(5)-(bromomethyl)pyrazole-5(3)-carboxylate (3) and 3(5)-(bromomethyl)pyrazole-5(3)-carboxamide (4) with poly-O-acetylated sugars via an acid-catalyzed fusion method afforded the corresponding ethyl 3-(bromomethyl)pyrazole-5-carboxylate and 3-(bromomethyl)pyrazole-5-carboxamide substituted nucleosides 5 and 7, respectively. In some cases, the positional isomers 6 and 8 were also obtained. Treatment of 5 and 7 with methanolic ammonia gave the deprotected 3-(aminomethyl)pyrazole-5-carboxamide nucleosides 9. Reaction of 3--5 and 7 with bis(2-chloroethyl)amine led to the corresponding pyrazole nitrogen mustards 10--13. All the bromomethylpyrazole nucleosides described showed significant cytostatic activity against HeLa cell cultures.

Antineoplastic Agents↗

PubMed1985

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

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

Animals↗

PubMedDate not supplied

Interaction of pyrazole and 4-methylpyrazole with hepatic microsomes: effect on cytochrome P-450 content, microsomal oxidation of alcohols, and binding spectra.

Microsomes isolated from rats treated with either pyrazole or 4-methylpyrazole, potent inhibitors of alcohol dehydrogenase, catalyzed the oxidation of ethanol and 2-butanol at rates 2-3-fold higher than saline controls. Time course experiments and dose-response experiments indicated that an increase in the microsomal oxidation of alcohols could be observed 24 hr after a single treatment with 200 mg/kg body weight of either pyrazole or 4-methylpyrazole, and after 2 or 3 days of treatment with 50 mg/kg of either of these compounds. The pyrazole treatment did not change the activity of NADPH-cytochrome P-450 reductase, the content of cytochrome P-450, or the oxidation of aminopyrine. Hence, microsomal oxidation of alcohols was increased by the pyrazole treatment whether results were expressed "per mg of protein" or "per nmol of P-450." Microsomes from the pyrazole-treated rats displayed an increase in binding spectrum with ethanol as the substrate as compared to controls, as well as type 2 binding spectrum with dimethyl sulfoxide and 2-butanol. These results suggest the possibility that pyrazole may induce an alcohol-preferring P-450 isozyme. By contrast, the 4-methylpyrazole treatment, besides increasing the oxidation of alcohols, also increased the oxidation of aminopyrine and the content of cytochrome P-450. The increase in the oxidation of alcohols and aminopyrine was primarily due to the increase in content of P-450 produced by the 4-methylpyrazole treatment. Binding spectra with dimethyl sulfoxide and 2-butanol were also observed after 4-methylpyrazole treatment; however, the 2-butanol-binding spectrum was a modified type 1 spectrum, not type 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗

PubMed1976

Effect of pyrazole, 4-methylpyrazole, 4-bromopyrazole and 4-iodopyrazole on brain noradrenaline levels of mice and rats.

Four daily doses of pyrazole (50 mg/kg), caused a reduction in rat brain noradrenaline (NA) of over 20% when determined 24 hrs after the final injection. Neither 4-methylpyrazole (10-50 mg/kg), nor 4-iodopyrazole (10-50 mg/kg) had any effect. In mice treated similarly, pyrazole (50-400 mg/kg) caused a dose-dependent decrease in brain NA. Neither 4-methylpyrazole, 4-bromopyrazole nor 4-iodopyrazole caused any significant change in the levels. However if the brain NA levels were examined 6 hrs after a single dose, then in addition to pyrazole, 4-methylpyrazole showed a dose-dependent ability to lower brain NA. 4-bromopyrazole and 4-iodopyrazole, given acutely, caused a dose-dependent decrease in rectal temperature and exploratory behaviour. 4-methylpyrazole in high doses (200-400 mg/kg) showed similar properties but they did not correlate with the decrease in brain NA. Pyrazole, after acute treatment, showed little ability to change rectal temperature of exploratory behaviour. It is concluded that the NA-depleting effect of pyrazole is not related to inhibition of alcohol dehydrogenase, since other 4-substituted pyrazoles which are more potent inhibitors of the enzyme have little or no effect on brain NA levels.

Animals↗

PubMed2003

Expression of CYP2A3 mRNA and its regulation by 3-methylcholanthrene, pyrazole, and beta-ionone in rat tissues.

Cytochrome P450 (CYP) 2A enzymes are involved in the metabolism of numerous drugs and hormones and activate different carcinogens. Human CYP2A6, mouse CYP2A5 and rat CYP2A3 are orthologous enzymes that present high similarity in their amino acid sequence and share substrate specificities. However, different from the human and mouse enzyme, CYP2A3 is not expressed in the rat liver. There are limited data about expression of CYP2A3 in extrahepatic tissues and its regulation by typical CYP inducers. Therefore, the objective of the present study was to analyze CYP2A3 mRNA expression in different rat tissues by RT-PCR, and to study the influence of 3-methylcholanthrene, pyrazole and -ionone treatment on its expression. Male Wistar rats were divided into four groups of 5 rats each, and were treated ip for 4 days with 3-methylcholanthrene (25 mg/kg body weight), pyrazole (150 mg/kg body weight), -ionone (1 g/kg body weight), or vehicle. Total RNA was extracted from tissues and CYP2A3 mRNA levels were analyzed by semiquantitative RT-PCR. CYP2A3 mRNA was constitutively expressed in the esophagus, lung and nasal epithelium, but not along the intestine, liver, or kidney. CYP2A3 mRNA levels were increased in the esophagus by treatment with 3-methylcholanthrene and pyrazole (17- and 7-fold, respectively), in lung by pyrazole and -ionone (3- and 4-fold, respectively, although not statistically significant), in the distal part of the intestine and kidney by 3-methylcholanthrene and pyrazole, and in the proximal part of the intestine by pyrazole. CYP2A3 mRNA was not induced in nasal epithelium, liver or in the middle part of the intestine. These data show that, in the rat, CYP2A3 is constitutively expressed in several extrahepatic tissues and its regulation occurs through a complex mechanism that is essentially tissue specific.

Animals↗

PubMed2000

Induction of mouse CYP2J by pyrazole in the eye, kidney, liver, lung, olfactory mucosa, and small intestine, but not in the heart.

We have recently shown that rat CYP2J4 is inducible by pyrazole in liver, small intestine, and olfactory mucosa. The aim of the present study was to determine whether mouse CYP2Js are also inducible by pyrazole, which was known to induce CYP2A5 in mouse liver and kidney, but not in lung or olfactory mucosa. CYP2J proteins were detected in mouse liver, lung, kidney, heart, eye, olfactory mucosa, and small intestine by immunoblot analysis with an anti-CYP2J4 antibody. The microsomal level of the CYP2J4-related P450s in various mouse tissues ranked in the order of small intestine > olfactory mucosa > liver > kidney > or = heart > lung > eye. Induction of the CYP2J proteins was observed in the eye, liver, lung, kidney, olfactory mucosa, and small intestine, but not in the heart, after daily i.p. injection of pyrazole at 120 or 200 mg/kg for 3 days. CYP2J proteins were induced similarly in C57BL/6 and DBA/2 mice. CYP2A5 was detected in the small intestine in addition to liver and olfactory mucosa; however, treatment with pyrazole induced CYP2A5 in the liver, but not in the olfactory mucosa or the small intestine. Induction of CYP2J mRNAs was also observed by RNA blot analysis with a CYP2J4 cDNA probe. RNA-polymerase chain reaction analysis showed that, in both untreated and pyrazole-treated mice, CYP2J5 was expressed in the kidney and liver, but not in the other tissues examined, whereas CYP2J6 was detected in all tissues examined. The different tissue selectivities in CYP2A5 and CYP2J induction by pyrazole suggest involvement of different regulatory mechanisms.

Animals↗

PubMedDate not supplied

Metabolism of pyrazole. Structure elucidation of urinary metabolites.

Pyrazole has been widely used as an inhibitor of alcohol dehydrogenase both in vivo and in vitro. Very little attention has been paid to the metabolism of this agent and possible biological activity of any metabolites. Several isotopic variants of pyrazole, both stable and radioactive, were used in a study of its metabolic fate by gas chromatography-mass spectrometry. Seven metabolites were structurally identified and included hydroxylated and conjugated derivatives of pyrazole. Two metabolites were conjugated with a pentose, perhaps indicating that pyrazole serves as a substrate in the salvage pathway of purines and pyrimidines forming pyrazole ribosides. The use of d3-pyrazole greatly enhanced structural assignment of the metabolites by revealing the metabolism at or next to a labeled carbon atom.

Animals↗

PubMed1991

Extremely long protection by pyrazole derivatives against chemically induced gastric mucosal injury.

We tested the hypothesis that the gastrotoxicity of ethanol and other damaging agents is influenced through the modulation of alcohol dehydrogenase (ADH) by using either the ADH-inhibitor pyrazole or the noninhibitor derivatives of pyrazole. In time course experiments, the protection by both compounds was evident up to 48 hr before ethanol administration. Both drugs were also protected, from about 24 hr, from gastric mucosal damage induced by aspirin and hydrochloric acid. In order to examine the role of endogenous prostaglandins and sulfhydryls in this protection, indomethacin and N-ethylmaleimide were used, of which only the sulfhydryl alkylator antagonized (by about 50%) the protection by pyrazole and 3-methylpyrazole. Studies with monastral blue B revealed the protective role of both pyrazole and 3-methylpyrazole against early vascular injury in the gastric mucosa. We conclude that because both the ADH-inhibitor pyrazole and the noninhibitor derivatives of pyrazole exert gastro-protection, and because both compounds protect against aspirin and HCI, ADH inhibition is not involved in this protection. We also suggest that although prostaglandins appear to have minimal involvement in the mechanism of protection, endogenous sulfhydryls may be important mediators. Furthermore, the functional and structural mechanism of this protection seems to be the prevention of acute vascular injury.

Amides↗

PubMed1990

1-phenyl-1H-pyrazole derivatives with antiinflammatory, analgesic and antipiretic activities.

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates 2 with phenylhydrazine gave the corresponding esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids 3 in high yields. Esters 3 were hydrolyzed to the relative carboxylic acids 4, which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles 5 in excellent yields. Reaction of methyl 5,5-dimethyl-3-dimethylaminomethylene-2,4-dioxohexanoate with phenylhydrazine afforded methyl 1-phenyl-4-pivaloyl-1H-pyrazole-5-carboxylate 8 b, which was converted as above to the corresponding carboxylic acid 10 b and this to 1-phenyl-4-pivaloyl-1H-pyrazole 11 b. Starting from 5-methoxymethyl-1-phenyl-1H-pyrazole, 1-phenyl-1H-pyrazole-5-acetic acid 18 and its alpha-methyl derivative 19 were also synthesized. Compounds 18, 19, 10 b and 11 b showed a strong antiinflammatory activity in rats; the same compounds in general as well as 8 b, showed appreciable analgesic and antipyretic activities in mice and rats, respectively.

Animals↗

PubMed1987

Pyrazoles as effectors of ethanol oxidizing enzymes and inducers of cytochrome P450.

The effectiveness of pyrazoles acting as inhibitors of alcohol dehydrogenase in vitro or of ethanol metabolism by intact, isolated hepatocytes is influenced both by the hydrophobicity of the pyrazole and by the electronic properties of the substituents at the 4-position of the pyrazole ring. In contrast, the binding of pyrazoles to cytochrome P450 in vitro and the induction of P450(s) in cultured hepatocytes are dependent only on hydrophobicity. The high correlation between the binding of pyrazoles in vitro and their ability to induce P450(s) in cultured liver cells suggests as a working hypothesis that the pyrazole:P450 complex has a role in the induction process.

Animals↗