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PubMed1986

Synthesis of 8-amino-3-deazaguanine via imidazole precursors. Antitumor activity and inhibition of purine nucleoside phosphorylase.

8-Amino-3-deazaguanine (15), an analogue of both 3-deazaguanine (1) and 8-aminoguanine (6), an antitumor agent and a purine nucleoside phosphorylase (PNP) inhibitor, respectively, was synthesized from the ammonolysis of an imidazole precursor, methyl 2-(benzoylamino)-5-(cyanomethyl)-1H-imidazole-4-carboxylate (13). The requisite imidazole, methyl 2-(benzoylamino)-4-(methoxycarbonyl)-1H-imidazole-5-acetate (11), was prepared from the monoheterocyclic rearrangement of dimethyl 3-[(5-phenyl-1,2,4-oxadiazol-3-yl)amino]-2-pentenedioate (10) by NaH/DMF. Ammonolysis and subsequent dehydration of 11 provided the penultimate imidazole intermediate 13. Its deprotected (NaOMe/100 degrees C) product, methyl 2-amino-5-(cyanomethyl)-1H-imidazole-4-carboxylate (14), was also converted to 15. 8-Amino-3-deazaguanine, as its methanesulfonic acid (mesylate 7), exhibited an inhibition constant (IC50) of 9.9 microM against isolated mammalian PNP. It was a very weak inhibitor of T and B cell growth and did not enhance 2'-deoxyguanosine toxicity in the same cells. 8-Amino-3-deazaguanine mesylate was not significantly active in L1210 cells in vitro or L1210 leukemic mice. Thus, the amino group introduced in the 8-position of 3-deazaguanine enhances its PNP activity but diminishes its antitumor activity.

Animals↗
PubMed1996

Efficient and beta-Stereoselective Synthesis of 4(5)-(beta-D-Ribofuranosyl)- and 4(5)-(2-Deoxyribofuranosyl)imidazoles(1).

A synthetic route to 4(5)-(beta-D-ribofuranosyl)imidazole (1), starting from 2,3,5-tri-O-benzyl-D-ribose (5), was developed via a Mitsunobu cyclization. Reaction of 5 with the lithium salt of bis-protected imidazole afforded the corresponding 5-ribosylimidazole 7RS. Hydrolysis of 7RS gave a 1:1 mixture of diol isomers 8R and 8S having an unsubstituted imidazole. Mitsunobu cyclization of the mixture 8RS using N,N,N',N'-tetramethylazodicarboxamide and Bu(3)P exclusively afforded benzylated beta-ribofuranosyl imidazole 9beta in 92% yield, accompanied by alpha-anomer 9alpha, in a ratio of 26.3:1. The configuration of 9beta was established by X-ray crystallography of ethoxycarbonyl derivative 10beta. Reductive debenzylation of 9beta over Pd/C was carried out, and the synthesis of 1 was attained from starting 5 in four steps and 87% overall yield. This synthetic methodology was extended to the synthesis of 4(5)-(2-deoxy-beta-D-ribofuranosyl)imidazole (2). Mitsunobu cyclization of a 1:1 mixture of the corresponding diol isomers 14RS produced 15beta and 15alpha in a ratio of 5.4:1. The synthesis of 2 was attained in a 59% overall yield from the starting 3,5-di-O-benzyl-2-deoxy-D-ribose (12). beta-Stereoselective glycosylation in the key step is discussed and explained by intramolecular hydrogen bonding between an NH in the imidazole and the oxygen functional group in the sugar moiety.

Journal Article↗
PubMed1985

In situ enzymatic reclosure of opened imidazole rings of purines in DNA damaged by gamma-irradiation.

When aqueous solutions of DNA were treated with 10-500 grays of gamma-rays, the imidazole rings of some adenine and guanine residues underwent scission, resulting in the conversion of these purines to formamidopyrimidines. It was found that formamidopyrimidine-DNA glycosylase, known to remove imidazole-ring-opened 7-methylguanine from DNA, did not excise the radiation-induced non-alkylated formamidopyrimidines formed for adenine and guanine. The repair of these ring-opened purines was found to involve an enzymatic recyclizing of the opened imidazole ring that effects a restoration of the C-8 to N-9 bond. The enzyme, purine imidazole-ring cyclase reclosed the imidazole rings of 90% of ring-opened adenine or guanine, but did not close the opened imidazole ring of 7-methylguanine-derived formamidopyrimidine in DNA.

Adenosine Triphosphate↗
PubMed1995

Structure of metal site in Cd-substituted His117Gly mutant of azurin with and without addition of imidazole derivatives.

The present work uses 111mCd-perturbed angular correlations of gamma-rays (PAC) to investigate the structure of the metal site of the His117Gly mutant of Pseudomonas aeruginosa azurin in aqueous solution and the effect on the structure upon addition of the following exogenous ligands: imidazole, 4-methyl imidazole, 1-methyl imidazole, 2-methyl imidazole and histidine. The nuclear quadrupole interaction of cadmium bound to the mutant without addition of exogenous ligands shows a strong pH dependence with three different nuclear quadrupole interactions consistent with two pKa values at about 7.2 and 8.6 at 2 degrees C. Addition of the imidazole derivatives resulted in a significant change in the PAC spectrum showing that they coordinate. This is in accordance with observations by EPR for the same mutant with copper at the metal site [den Blaauwen, T. & Canters, G. W. (1993) J. Am. Chem. Soc. 115, 1121-1129]. However, whereas EPR and ultraviolet/visual absorption show that the characteristics of the wild-type copper protein are regained by addition of the imidazole derivatives with the exception of the possible bidentates (histidine and histamine), the comparison of the PAC results to model calculations shows that the cadmium ion must be fourfold coordinated in most cases, probably binding an additional water or hydroxide ligand. A fourfold coordination is in contrast to cadmium-substituted wild-type azurin where PAC data inferred a threefold coordination by a Cys and two His residues [Danielsen, E. Bauer, R., Hemmingsen, L., Andersen. M., Bjerrum, M. J., Butz, T., Tröger, W., Canters, G. W., Hoitink, C. W. G., Karlsson, G., Hansson, O. & Messerschmidt, A. (1995) J. Biol. Chem. 270, 573-580]

Azurin↗
PubMed1996

Protonation sites in gaseous pyrrole and imidazole: a neutralization-reionization and ab initio study.

Mild gas-phase acids C4H9+ and NH4+ protonate pyrrole at C-2 and C-3 but not at the nitrogen atom, as determined by deuterium labeling and neutralization-reionization mass spectrometry. Proton affinities in pyrrole are calculated by MP2/6-311G(2d,p) as 866, 845 and 786 kJ mol-1 for protonation at C-2, C-3 and N, respectively. Vertical neutralization of protonated pyrrole generates bound radicals that in part dissociate by loss of hydrogen atoms. Unimolecular loss of hydrogen atom from C-2- and C-3-protonated pyrrole cations is preceded by proton migration in the ring. Protonation of gaseous imidazole is predicted to occur exclusively at the N-3 imine nitrogen to yield a stable aromatic cation. Proton affinities in imidazole are calculated as 941, 804, 791, 791 and 724 for the N-3, C-4, C-2, C-5 and N-1 positions, respectively. Radicals derived from protonated imidazole are only weakly bound. Vertical neutralization of N-3-protonated imidazole is accompanied by large Franck-Condon effects which deposit on average 183 kJ mol-1 vibrational energy in the radicals formed. The radicals dissociate unimolecularly by loss of hydrogen atom, which involves both direct N-H bond cleavage and isomerization to the more stable C-2 H-isomer. Potential energy barriers to isomerizations and dissociations in protonated pyrrole and imidazole isomers and their radicals were investigated by ab initio calculations.

Imidazoles↗
PubMed1990

Studies on the effects of imidazole on the peroxyoxalate chemiluminescence detection system for high performance liquid chromatography.

The catalytic effect of bases (imidazole, pyridine, Tris and triethylamine) on the peroxyoxalate chemiluminescence (PO-CL) reaction for high performance liquid chromatography (HPLC) was investigated. Imidazole increased PO-CL intensity extraordinarily, whereas the other bases (pyridine, Tris and triethylamine) did not. The peak heights of dipyridamole (coronary vasodilator) obtained using the eluents containing buffers were largest at pH 7.0, a few times less at pH 6.0 and pH 5.0, 100 times less at pH 4.0 and a few hundred times less at pH 3.0. The eluents containing buffers at pH 3, 4, 5, 6 or 7 each with imidazole increased the peak heights by a few to ten times as compared with those without imidazole, and those peak heights were within one order of magnitude. On the other hand, the eluent containing buffer at pH 2 did not affect the peak heights with or without imidazole. Bis(4-nitro-2-(3,6,9-trioxadecyloxycarbonyl)phenyl) oxalate (TDPO) alone and bis(2,4-dinitrophenyl)oxalate (DNPO) plus TDPO were recommended to be used against eluents containing buffers of pH 5-7 and pH 3-4, respectively. Dipyridamole and benzydamine hydrochloride (anti-inflammatory drug) were separated on the ODS column and detected by the present system. The detection limits of dipyridamole and benzydamine hydrochloride were 40 amol and 270 fmol, respectively.

Chromatography, High Pressure Liquid↗
PubMed1982

Dissociation of hemoglobin accumulation and commitment during murine erythroleukemia cell differentiation by treatment with imidazole.

The effect of imidazole on DMSO-induced murine erythroleukemia (MEL) cell differentiation has been examined. While imidazole does inhibit heme, globin mRNA, and hemoglobin accumulation in DMSO-induced MEL cells, it does not affect the commitment of MEL cells to the specific limitation of proliferative capacity associated with the in vitro differentiation program. Furthermore, imidazole treatment does not affect DMSO-induced changes in cell volume, in the relative proportion of nuclear protein IP25, and in the specific activity of the enzyme cytidine deaminase. A clonal analysis in the presence of imidazole indicated that the drug prevents heme accumulation even in MEL cells already committed to terminal differentiation. These observations suggest that imidazole effectively dissociates two aspects of the erythroid differentiation program of MEL cells: globin gene expression and commitment to loss of proliferative capacity.

Animals↗
PubMed1994

The inhibition of the constitutive bovine endothelial nitric oxide synthase by imidazole and indazole agents.

Citrulline formation by the Ca2+ CaM-dependent nitric oxide synthase of bovine endothelium is inhibited reversibly by 7-nitroindazole, 1-phenylimidazole, and imidazole. As measured at 0.67 microM (6R)-5,6,7,8-tetrahydrobiopterin (BH4), IC50 values of 0.8, 200, and 50 microM were determined for 7-nitroindazole, 1-phenylimidazole, and imidazole, respectively. Increasing concentrations of added BH4 cofactor increased the IC50 values for 7-nitroindazole and 1-phenylimidazole but did not alter the IC50 value for imidazole. 7-nitroindazole inhibited citrulline formation by the endothelial cNOS noncompetitively versus arginine substrate but competitively versus BH4 with a Ki value of 0.8 microM. 1-Phenylimidazole inhibited citrulline formation by the endothelial cNOS competitively versus both arginine substrate and BH4 with a Ki value of 50 microM. Imidazole inhibited citrulline formation competitively versus arginine substrate but noncompetitively versus BH4 with a Ki value of 50 microM. Neither 7-nitroindazole, 1-phenylimidazole, nor imidazole inhibited the cytochrome c reductase activity of endothelial cNOS at concentrations up to 5000-fold higher than their Ki values for inhibition of citrulline formation. By comparison with the previously determined kinetic properties of the other nitric oxide synthase isoforms, these observations establish that 1-phenylimidazole displays marked specificity for inhibiting the inducible nitric oxide synthase isoform and, since 7-nitroindazole has been reported not to elevate blood pressure (McCall et al., 1991, Br. J. Pharmacol. 102, 234-238), fails to confirm the expected insensitivity of the constitutive endothelial nitric oxide synthase to inhibition by 7-nitroindazole.

Amino Acid Oxidoreductases↗
PubMed1996

Oxygen-centered spin adducts of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and 2H-imidazole 1-oxides.

The hydroxyl and some alkoxyl spin adducts of 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) are difficult to assign due to the remarkable similarity of their EPR spectra. The utility of resolving superhyperfine (SHF) structure followed by computer simulations has been demonstrated to assist in the assignment of EPR spectra with close values of hyperfine splitting constants, e.g., DMPO/ .OH and DMPO/.OR. Here, .OR is the alkoxyl radical derived from thermal decomposition of 2,2' -azobis (2-amidinopropane) hydrochloride (AAPH). In addition, two other spin traps, derivatives of 2H-imidazole 1-oxide, namely, 2,2,4-trimethyl-2H-imidazole 1-oxide (TMIO) and 2,2-dimethyl-4-phenyl-2H-imidazole 1-oxide (DMPIO), have been used in a model study to develop a procedure for distinguishing between oxygen-centered spin adducts. These results are compared with those for DMPO. TMIO and DMPIO spin traps provide more distinguishable individual spectra with .OH and AAPH-derived .OR radicals than the DMPO spin trap. The formation of DMPO/.OR(AAPH) and DMPIO/ .OR(AAPH) spin adducts was confirmed by mass spectrometry. The comparison of spin trapping by DMPO and 2H-imidazole 1-oxides using typical biological sources of other oxygen-centered radicals reveals application limits of these spin traps. For example, 2H-imidazole 1-oxides do not form superoxide spin adducts in the xanthine/xanthine oxidase system. Also, for the first time, experimental evidence is presented for SHF structure in spectra of TMIO and DMPIO spin adducts with .OH/.OD and .CH3/ .CD3 radical species.

Animals↗
PubMed1993

Resistance to imidazoles and triazoles in Saccharomyces cerevisiae as a new dominant marker.

The imidazole and triazole fungicides inhibit cytochrome P450 14 alpha-lanosterol demethylase (P45014DM) implicated in the ergosterol biosynthesis pathway, which is specific to fungi and yeasts. Two plasmids were obtained which allow triazole and imidazole resistance in Saccharomyces cerevisiae. The low copy number plasmid (pFD 383) encodes cytochrome P450 C14 alpha lanosterol demethylase under the control of phospho-glycerate-kinase promoter. S. cerevisiae transformed by the pFD 383 plasmid are resistant to imidazoles and triazoles. Moreover, this transformed strain shows increased levels of P45014DM mRNA and of cytochrome P450. A second low copy number plasmid (pFD 384) carries a mutant cytochrome P450 14 alpha lanosterol demethylase gene, which increases imidazole and triazole resistance. These constructions can be used on a dominant selection marker to transform wild-type yeasts and to confer imidazole and triazole resistance in industrial fermentation.

Antifungal Agents↗
PubMed1982

Imidazole-buffered osmium tetroxide: an excellent stain for visualization of lipids in transmission electron microscopy.

The usefulness of imidazole-buffered osmium tetroxide as a stain for lipids in transmission electron microscopy has been investigated. Rat liver and other tissues were fixed by perfusion with glutaraldehyde and post-fixed with osmium-imidazole and the appearance of lipid droplets was compared with that after post-fixation in unbuffered aqueous osmium tetroxide or an osmium solution buffered otherwise. Prominent electron-opaque staining of lipid droplets and of lipoprotein particles was noted after post-fixation with 2% osmium-imidazole, pH 7.5, for 30 min. The lipid droplets appeared well circumscribed with no evidence of diffusion. In contrast, the intensity of staining was much less and there was some diffusion around lipid droplets in material post-fixed in aqueous or cacodylate-buffered osmium tetroxide. Spot tests on filter paper revealed that unsaturated fatty acids, especially linolenic and linoleic acids reacted more intensely with osmium-imidazole than with aqueous osmium tetroxide. These findings demonstrate that osmium-imidazole provides an excellent stain for lipids in transmission electron microscopy and that most probably it stains lipids with unsaturated fatty acids.

Adipose Tissue, Brown↗
PubMed2002

Replacement of imidazole by a piperidine moiety differentially affects the potency of histamine H3-receptor antagonists.

We examined whether replacement of imidazole by a piperidine or pyrrolidine moiety will affect the potency and affinity of six H3-receptor antagonists. Potencies were determined in superfused mouse brain cortex slices preincubated with [3H]noradrenaline, in which the interaction of the antagonists with histamine with respect to its inhibitory effect on the electrically evoked tritium overflow was studied. Affinities were determined in mouse brain cortex membranes, using the radioligand [3H] N(alpha)-methylhistamine. The concentration-response curve of histamine for its effect on the evoked overflow from mouse brain cortex slices was shifted to the right by the 13 compounds under study. Replacement of the imidazole by a piperidine ring affected the p A2 value as follows: thioperamide, -2.7 log units; clobenpropit, -1.9; proxyfan, -1.3; FUB 138, -1.2. Potency hardly changed (< or =0.4 log units) when imidazole was replaced by piperidine in FUB 181 and by piperidine or pyrrolidine in FUB 153. Binding of [3H] N (alpha)-methylhistamine to mouse brain cortex membranes was inhibited monophasically by all compounds. The p K(i) values closely matched their p A2 values with three exceptions. The p K(i) values of proxyfan, FUB 138, and FUB 153 exceeded their respective p A(2) values by about 1 log unit. To reveal a potential partial agonism, the effect of the three drugs on (1) the electrically evoked tritium overflow and (2) [35S]GTPgammaS binding in mouse cortex preparations was determined. Proxyfan proved to be a partial agonist in both models (with intrinsic activities of 0.2 and 0.3, respectively) whereas FUB 138 and FUB 153 were devoid of agonistic effects. In conclusion, replacement of imidazole by piperidine or pyrrolidine affects the antagonist potencies of six H3-receptor antagonists in a very different manner. The piperidine analogue of FUB 181 (with a p A2 value as high as 7.7) may represent a lead for the development of non-imidazole H3-receptor antagonists. The discrepancy between the p K(i) and p A2 values may be accounted for by partial agonism in the case of proxyfan but can, at present, not be satisfactorily explained with respect to FUB 138 and FUB 153.

Animals↗
PubMed1975

Studies on the heme environment of horse heart ferric cytochrome c. Azide and imidazole complexes of ferric cytochrome c.

Horse heart ferric cytochrome c was investigated by the following three methods: (I) Light absorption spectrophotometry at 23 degrees C and 77 degrees K; (II) Electron paramagnetic resonance (EPR) spectroscopy at 20 degrees K; (III) Precise equilibrium measurements of ferric cytochrome c with azide and imidazole between 14.43 and 30.90 degrees C. I and II have demonstrated that: (1) Ferric cytochrome c azide and imidazole complexes were in the purely low spin state between 20 degrees K and 23 degrees C; (2) The energy for the three t2g orbitals calculated in one hole formalism shows that azide or imidazole bind to the heme iron in a similar manner to met-hemoglobin azide or imidazole complexes, respectively. III has demonstrated that: (1) The change of standard enthalpy and that of standard entropy were -2.3 kcal/mol and -1.6 cal/mol per degree for the azide complex formation, and -1.4 kcal/mol and 2.9 cal/mol per degree for the imidazole complex formation. (2) A linear relationship between the change of entropy and that of enthalpy was observed for the above data for the cyanide complex formation. The complex formation of ferric cytochrome c was discussed based on the results of X-ray crystallographic studies compared with hemoglobin and myoglobin.

Animals↗
PubMed1988

Comparative effects of antithrombitic and antimycotic N-substituted imidazoles on rat hepatic microsomal steroid and xenobiotic hydroxylases in vitro.

N-Substituted imidazoles have been shown to be potent inhibitors of microsomal mixed-function oxidase activities in vitro and in vivo. In the present study the effects of two antithrombitic (dazmegrel and dazoxiben) and four antimycotic (ketoconazole, econazole, miconazole and clotrimazole) imidazoles on microsomal cytochrome P-450-mediated steroid and xenobiotic hydroxylases were studied in vitro. Despite the presence of the N-substituted imidazole moiety, the antithrombitic agents were essentially non-potent as inhibitors of all of the oxidase activities evaluated. In contrast, the antimycotic drugs were potent inhibitory compounds. Binding studies revealed that all six imidazoles elicited type II optical difference spectra and exhibited relatively high affinity for ferricytochrome P-450 in microsomal suspensions (Ks range 0.26-0.73 microM for the antimycotic agents and 6.5 microM and 21 microM for dazmegrel and dazoxiben, respectively). The structural feature that the antithrombitic compounds share is a carboxylate function so that, at physiological pH, less than 1% of the drug would be present in the unionised form. This functionality is absent from the structures of the antimycotic agents which possess much greater hydrophobic character. Even though the antithrombitic imidazoles elicit type II binding interactions of quite high affinity it would appear from this study that significant inhibition potency does not necessarily follow. The present findings also suggest that interesting differences exist between the active site binding regions in the cytochrome P-450 that catalyse thromboxane synthetase activity and those involved in microsomal drug oxidation. Inhibitor hydrophobicity is clearly an important factor in the inhibition of microsomal cytochromes P-450 whereas effective thromboxane synthetase inhibitors may be quite hydrophilic at physiological pH.

Animals↗
PubMed1989

Inhibition of beta-glucosidase by imidazoles.

Over 25 nitrogen-containing heterocycles were tested as inhibitors of sweet almond beta-glucosidase (EC 3.2.1.21). Among the most potent of these are some imidazole derivatives. The pH dependence indicates that the unprotonated inhibitor binds most tightly to the catalytically active species of the enzyme. This is analogous to the situation with 1-deoxynojirimycin where the permanently cationic species, N,N-dimethyl-1-deoxynojirimycin, binds at least two orders of magnitude less tightly to the enzyme than does the unprotonated 1-deoxynojirimycin. The binding of imidazole derivatives show a general tendency of increasing affinity with increasing basicity (beta approximately 0.4). One derivative which shows a significant positive deviation from this correlation (- log Ki vs. pKa) is 4-phenylimidazole. 4-Phenylimidazole is one of the most potent reversible inhibitors of beta-glucosidase with a pH-independent Ki = 0.8 microM. It is also fairly specific for beta-glucosidase, binding at least three orders of magnitude less tightly to any of the other exoglycosidases tested. This inhibitor combines, in a mono-molecular species, the binding affinities of benzene, which binds at the hydrophobic aglycone binding site, and imidazole, which binds at the sugar binding site of beta-glucosidase. The binding energy of 4-phenylimidazole can be attributed to the sum of the intrinsic binding energies of the phenyl and imidazole moieties. Thus, there is no significant entropic advantage of combining the component parts of phenylimidazole in a single species. This indicates that there is no significant uncompensated entropy loss upon binding of either benzene or imidazole to the enzyme. Nevertheless, the additivity of binding energy, even in the absence of an entropic advantage, results in the most powerful known inhibitor of the enzyme.

1-Deoxynojirimycin↗
PubMed1994

Pyridinyl imidazoles inhibit the inflammatory phase of delayed type hypersensitivity reactions without affecting T-dependent immune responses.

The effects of pyridinyl imidazoles, specifically SK&F 105809 and its metabolite, on normal T-cell and B-cell mediated immune responses were examined and compared to the fungal macrolide immunosuppressives, cyclosporin A, FK506 and rapamycin and to the corticosteroid, dexamethasone. The orally active prodrug SK&F 105809 [2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo [1,2-a] imidazole[ and its metabolite, SK&F 105561 [2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a] imidazole] are dual 5-lipoxygenase (5-LO) and cycloxygenase (CO) inhibitors with potent anti-inflammatory and cytokine (IL-1/TNF) suppressive activities. The anti-inflammatory activity of SK&F 105809 and its metabolite were evaluated in an antigen-specific murine model of delayed type hypersensitivity (DTH) response, where they were found to affect only the inflammatory and not the induction phase of this response. In contrast, these compounds and other pyridinyl imidazoles (SK&F 86002 and its analog, SK&F 104351) exhibited no immunosuppressive activity under conditions where the macrolide rapamycin and the corticosteroid dexamethasone abrogated both the cellular and humoral immune responses. Thus, the ability of pyridinyl imidazoles to attenuate independently the inflammatory components of the disease without causing generalized immunosuppression enhances their profile as candidates for therapy of chronic inflammatory diseases, specifically those mediated by cytokines (e.g. IL-1, TNF) and eicosanoids.

Animals↗
PubMed1976

Effect of imidazole on renal gluconeogenesis.

The metabolic effects of imidazole were tested in rat renal cortex. Imidazole enhanced the activity of renal cortical phosphodiesterase in vitro. Imidazole inhibited glucose production in a dose-dependent fashion from a variety of substrates in the gluconeogenic pathway proximal to the triose phsophates. The stimulation in renal gluconeogenesis resulting from isoproterenol and parathyroid hormone was inhibited by imidazole. These changes correlated with an inhibition of the augmented levels of renal cortical cyclic AMP levels produced by these hormones. These studies indicate that imidazole is an effective activator of phosphodiesterase in intact renal cells and lend further support to the suggestion that the stimulation of renal gluconeogenesis produced by isoproterenol and parathyroid hormone is mediated by a release of cyclic AMP.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Induction of hepatic oxidative and conjugative drug metabolism in the hamster by N-substituted imidazoles.

Three antimycotic N-substituted imidazoles, clotrimazole, tioconazole and miconazole, were able to induce hepatic microsomal cytochrome P-450 and monooxygenase reactions in both male and female hamsters to an extent similar to that seen with phenobarbital treatment. Imidazole treatment did not alter the cytochrome P-450 concentration, and ketoconazole treatment decreased it. Cytosolic sulfo- and glutathione transferases were not significantly altered by any imidazole. Induction of microsomal morphine glucuronosyltransferase activity by each compound generally paralleled the effect on cytochrome P-450 in females but induction was not evident in males. Clotrimazole treatment, in contrast to phenobarbital treatment, also caused a large induction of l-naphthol glucuronosyltransferase in females. The potential for antimycotic imidazoles to alter the hepatotoxicity of compounds will require consideration of the inductive changes in both Phase I and Phase II drug metabolizing enzymes in addition to their known inhibitory effects on Phase I oxidations. The inductive effects differ for each imidazole, and in the hamster model, depend upon the sex of the animal.

Animals↗