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PubMed2005

Coupling properties of imidazole dimer radical cation assisted by embedded water molecule: toward understanding of interaction character of hydrogen-bonded histidine residue side-chains.

Geometry optimizations are performed at the DFTB3LYP6-311+G* level. Four intriguing coupling modes, totally eight stable structures are found in the potential energy surfaces of the water-assisted coupling of imidazole dimer radical cation. In these isomers, the water molecules are embedded between two imidazole moieties, and the oxygen atom is tridentate or quadridentate, respectively. The distinct redshifts of the vibrational frequencies of the O-H...N and N-H...O type H bonds indicate the strong interaction of two imidazole rings of respective isomer. Inspection of the highest occupied molecular orbital predicts the alterations of the geometry structures on oxidation and reduction. The low barrier of the fragment rotation demonstrates that the isomerization processes by experiencing the distinct transition states are easy to fulfill, especially for those with O-H...N and C-H...O H bonds. Both the energy difference of the 0 degrees-cis and 180 degrees-trans orientation and the barriers of the fragment rotation are lowered by the water assisting. The range of the zero point vibrational energy correction indicates that the influence on the complexes with N-H...O and O-H...N H bonds (0.13-0.17 kcal/mol) is more significant than those with O-H...N and C-H...O H bonds (+/-0.03 kcal/mol). The dissociation energies of these isomers indicate that the charges transfer easily through water in the dissociation process and then are distributed mainly over the imidazole ring connecting with water molecule. The isomer with proton transfer between imidazole fragments is the most stable one.

Cations↗

PubMed1977

Application of imidazole as a selective inhibitor thromboxane synthetase in human platelets.

Human platelet suspensions release a rabbit-aorta-contracting substance (previously identified as thromboxane A2) during aggregation produced by arachidonic acid, prostaglandin endoperoxide, thrombin, and collagen. Incubation of platelets with imidazole did not interfere with the aggregation produced by these agonists but markedly reduced the generation of the rabbit-aorta-contracting substance. We find that imidazole inhibited the conversion of exogenous or endogenous prostaglandin endoperoxide into thromboxane A2-Imidazole selectively inhibits thromboxane synthetase in intact human platelets, because this agent blocks the conversion of [14C]arachidonate into [14C]thromboxane B2 but does not inhibit the conversion of [14C]arachidonate into [14C]prostaglandin E2. The inhibition of thromboxane synthetase by imidazole is not the result of an alteration in platelet 3':5'-cyclic AMP levels. These results illustrate the utility of imidazole as a pharmacological tool and demonstrate the two unique and dissociable properties of the endoperoxides themselves--their ability to aggregate platelets and their enzymatic conversion to the potent vasoconstrictor thromboxane.

Blood Platelets↗

PubMed1989

On the mechanism of action of ribonucleases: dinucleotide cleavage catalyzed by imidazole and Zn2+.

Cyclization/cleavage of the 2-(p-nitrophenyl) phosphate ester of propylene glycol is catalyzed by imidazole and, much more effectively, by Zn2+ with imidazole. In the latter case, the mechanism involves simultaneous Lewis acid/base catalysis. Similar Zn2+ and imidazole catalysis of cyclization/cleavage is seen with the dinucleotide 3',5'-UpU (uridylyluridine). Again, the zinc system is much more effective than is catalysis by imidazole alone, and in this case simultaneous Lewis acid/base catalysis substitutes for the sequential proton acid/base catalysis seen with polynucleotides or dinucleotides and imidazole buffer catalysts. A mechanism is proposed for catalysis of RNA cleavage by the enzyme ribonuclease A, and the relationship of that mechanism to the action of the enzyme model systems is discussed.

Catalysis↗

PubMed1983

Excision of aflatoxin B1-imidazole ring opened guanine adducts from DNA by formamidopyrimidine-DNA glycosylase.

This investigation has confirmed the earlier reports that when aflatoxin B1-DNA adducts are stored under physiological conditions some aflatoxin B1-guanine adducts are converted to a secondary product in which fission of the imidazole ring of the adduct guanine has occurred. Incubation of DNA containing aflatoxin B1-guanine adducts for an increasing number of hours under physiological conditions resulted in a progressive increase in the number of adducts in which the imidazole rings of guanines underwent fission. It was shown that the Escherichia coli enzyme, formamidopyrimidine-DNA glycosylase exercises from the 6-day incubated DNA, an amount of imidazole ring opened guanines equivalent to 40% of the aflatoxin B1-guanine adducts present in the DNA. The enzymatic excision of imidazole ring opened aflatoxin B1-guanine adducts is inhibited by Cibacron Blue F3GA a strong inhibitor of formamidopyrimidine-DNA glycosylase. Treatment of aflatoxin B1-DNA with mild alkali (pH 9.6), resulted in a 2-fold increase in the amount of aflatoxin B1-guanines with opened imidazole rings; this was revealed by enzyme assays using this alkaline treated DNA substrate as well as by analysis of acid hydrolysates of the alkaline treated DNA.

Aflatoxin B1↗

PubMed1991

Interactions in vitro between polyenes and imidazoles against yeasts.

The polyenes, amphotericin B and mepartricin and the imidazoles, miconazole, ketoconazole, itraconazole and fluconazole, were studied either alone or in paired polyene-imidazole combinations to determine their activity in vitro against clinical yeast isolates. The methods included shaken and standing liquid cultures, continuous cultures and chequerboard titrations, with or without the incorporation of pooled human plasma. The polyenes were found to exert an immediate cidal action even with high cell populations whereas the imidazoles demonstrated a time-dependent fungistatic activity which increased very slowly with increase in drug concentration. The interactions observed with the paired combinations were consistent and were found to be anomalous with all methods used. The activity of the imidazoles was enhanced by the presence of the polyenes; by contrast the polyenes were strongly antagonized by the imidazoles.

Antifungal Agents↗

PubMed1999

Characterization of imidazole as a DNA denaturant by using TGGE of PCR products from a random pool of DNA.

Perpendicular temperature gradient gel electrophoresis (TGGE) profiles were analyzed for PCR products from a random pool of DNA [60 nts random region flanked by two primer (20 nts) sites]. Besides a normal transition profile of a homoduplex, unique mobility transition profiles of two kinds of heteroduplex with a big internal loop were observed, representing the successive helix-coil transitions of the DNAs. As the appearance of the heteroduplex band is an estimator of the complexity of a random pool, it will be applicable to monitor the extent of the selection process in the in vitro selection method. When imidazole was added to the electrophoretic buffer, the transition pattern shifted to the low temperature side. At a concentration of 1 M, imidazole lowered the melting temperature (Tm) of DNA by 13+/-2 degrees C for all the three chain separation transitions observed. Thus imidazole is a stronger denaturant than urea, at least at dilute concentration. Dependence of Tm on concentration of imidazole and the mobility change suggested that imidazole binds to nucleotide in the single-stranded state.

Base Sequence↗

PubMed1998

Imidazoles suppress rat testosterone secretion and testicular interstitial fluid formation In vivo.

The aim of these studies was to examine the effects of imidazoles on testosterone secretion and testicular interstitial fluid (TIF) formation through measurement of serum LH, serum testosterone, TIF testosterone, and TIF volumes. Imidazole, 1-methylimidazole, 4-methylimidazole (4-MI), and ketoconazole, an oral imidazole antifungal agent, caused dose-dependent decreases in testosterone secretion and TIF formation. Imidazole, 2-methylimidazole, and 4-MI decreased LH secretion. 4-MI decreased testosterone secretion 1-6 h after injection, increased testosterone at 8-16 h, decreased LH secretion at 4 h, decreased TIF volumes at 1-8 h, and slightly increased TIF volumes at 24 h. 4-MI blocked the stimulatory effects of hCG on testosterone secretion and prevented an expected increase in LH secretion after the 4-MI-induced decrease in testosterone secretion. 4-MI also reversed the effects of three other stimulants of testosterone secretion that presumably act through three different testicular regulatory systems: N-methyl-D,L-aspartate, an excitatory amino acid; NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor; and naltrexone, an opioid antagonist. These results support the hypothesis that imidazoles inhibit testicular function and male reproductive function through inhibition of testosterone secretion, TIF formation, and LH secretion regulatory systems.

Animals↗

PubMed1988

Hypotensive action of clonidine analogues correlates with binding affinity at imidazole and not alpha-2-adrenergic receptors in the rostral ventrolateral medulla.

Clonidine acts within the rostral ventrolateral medulla to lower arterial pressure. The receptor mechanism for this action is unknown. In the rostral ventrolateral medulla clonidine binds not only to the alpha 2-adrenergic receptor but also to a novel class of sites which are specific for imidazolines and imidazoles and are distinct from adrenergic or histaminergic receptors. In order to distinguish whether a putative imidazole receptor or the alpha 2-receptor mediates the clonidine hypotensive response, a series of clonidine analogues were tested (1) in radioligand binding assays of their affinity at imidazole and alpha 2-adrenergic receptors, and (2) by microinjection into the rostral ventrolateral medulla of anaesthetized rats to measure their capacity to lower arterial pressure. The hypotensive response elicited by the test agents was strongly correlated with affinity at imidazole sites (r = 0.92) but not with alpha 2-adrenergic affinity (r = 0.36). An imidazole receptor in the rostral ventrolateral medulla may participate in the hypotensive action of clonidine.

Animals↗

PubMed1977

The effects of alloxanate, nicotinic acid and imidazole on secretory processes and the activities of adenylate cyclase and 3',5'-AMP phosphodiesterase in cat pancreas.

1 Nicotinic acid and alloxanate inhibited water and electrolyte secretion in a dose-dependent fashion when added to the perfusate of the isolated saline-perfused pancreas of the cat stimulated by a supramaximal dose of secretin.2 There were no changes in the concentration of sodium or potassium secreted into the juice, but the anions exhibited changes which were related to flow rate. As the flow rate declined the chloride concentration increased with a reciprocal decrease in bicarbonate concentration.3 Nicotinic acid and alloxanate inhibited enzyme secretion stimulated by carbachol.4 Imidazole inhibited pancreatic electrolyte secretion, but stimulated amylase secretion. Atropine (0.14 muM) reduced the secretion of amylase but did not abolish the effect.5 Adenylate cyclase prepared from cat pancreas, was stimulated by the octapeptide of cholecystokinin-pancreozymin, secretin and sodium fluoride.6 Alloxanate strongly inhibited both basal and hormone-stimulated adenylate cyclase activity. Nicotinic acid and imidazole stimulated basal adenylate cyclase activity but had little effect on secretin-stimulated activity.7 Alloxanate, nicotinic acid and imidazole were all without effect on phosphodiesterase when tested in the presence of micromolar concentrations of adenosine 3',5'-monophosphate (cyclic AMP). At higher cyclic AMP concentrations (2 mM) alloxanate and nicotinic acid were without effect, whereas imidazole had a slight stimulatory effect at 10 mM which was more marked at 50 mM.8 Alloxanate (10 mM) strongly inhibited both basal and secretin-stimulated adenylate cyclase activity.9 It is concluded that the effects of nicotinic acid, alloxanate and imidazole on pancreatic secretion are not mediated entirely through their effects on the adenylate cyclase or phosphodiesterase enzyme systems.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1996

Inhibition of nitric oxide synthase by 1-(2-trifluoromethylphenyl) imidazole (TRIM) in vitro: antinociceptive and cardiovascular effects.

1. The ability of a range of substituted imidazole compounds to inhibit mouse cerebellar neuronal nitric oxide synthase (nNOS), bovine aortic endothelial NOS (eNOS) and inducible NOS (iNOS) from lungs of endotoxin-pretreated rats was investigated. In each case the substrate (L-arginine) concentration employed was 120 nM. 2. 1-(2-Trifluoromethylphenyl) imidazole (TRIM) was a relatively potent inhibitor of nNOS and iNOS (IC50S of 28.2 microM and 27.0 microM respectively) but was a relatively weak inhibitor of eNOS (IC50, 1057.5 microM). The parent compound, imidazole, was a weak inhibitor of all three NOS isoforms (IC50S: nNOS, 290.6 microM; eNOS, 101.3 microM; iNOS, 616.0 microM). Substitution of imidazole with a phenyl group to yield I-phenylimidazole (PI) resulted in an isoform non-selective increase in inhibitory potency (IC50S: nNOS, 72.1 microM; eNOS, 86.9 microM; iNOS, 53.9 microM). Further substitution of the attached phenyl group resulted in an increase in nNOS and a decrease in eNOS inhibitory potency as in TRIM, 1-chlorophenylimidazole (CPI; IC50S: nNOS, 43.4 microM; eNOS, 392.3 microM; iNOS, 786.5 microM) and 1-(2,3,5,6-tetrafluorophenyl) imidazole (TETRA-FPI; IC50S; nNOS, 56.3 microM; eNOS, 559.6 microM; iNOS, 202.4 microM). 3. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was influenced by the concentration of L-arginine (0.12-10.0 microM) in the incubation medium. When mouse cerebellar nNOS was used as enzyme source a double reciprocal (Lineweaver-Burk) plot in the presence/absence of TRIM (50 microM) revealed a competitive inhibitory profile. The K(m) for L-arginine and the Ki for TRIM calculated from these data were 2.4 microM and 21.7 microM, respectively. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was unaffected by varying the time of exposure of the enzyme to TRIM from 0-60 min at 0 degree C. 4. TRIM exhibits potent antinociceptive activity in the mouse as evidenced by inhibition of acetic acid induced abdominal constrictions. The ED50 for TRIM following i.p. administration was 20 mg kg-1 (94.5 mumol kg-1). The antinociceptive effect of TRIM was reversed by pretreatment of animals with L-arginine (50 mg kg-1, i.p.) and was not accompanied by sedation, motor ataxia or behavioural changes (rearing, crossing, circling, dipping) as assessed by use of a box maze procedure. 5. L-NG nitro arginine methyl ester (L-NAME, 20 mg kg-1, i.v.) but not TRIM (0.5-20 mg kg-1, i.v.) increased mean arterial blood pressure (MAP) in the urethane-anaesthetized rat. 6. L-NAME (100 microM) potentiated the contractile response of the rabbit isolated aorta to phenylephrine (ED50; 0.084 +/- 0.01 microM in the presence and 0.25 +/- 0.05 microM in the absence of L-NAME; maximum response, 7.7 +/- 0.4 g in the presence and 5.6 +/- 0.5 g in the absence of L-NAME, n = 6, (P < 0.05) whilst TRIM (1-100 microM) was without effect. L-NAME (100 microM) but not TRIM (1-100 microM) also reduced carbachol-induced relaxation of the phenylephrine-precontracted rabbit aorta preparation. 7. L-NAME (50 microM) potentiated the vasoconstrictor effect of bolus-injected noradrenaline (10-1000 nmol) and reduced the vasodilator effect of carbachol (10 microM) added to the Krebs reservoir in the rat perfused mesentery preparation. L-NAME (50 microM) also reduced nitric oxide (NO) release (measured by chemiluminescence of nitrite in the Krebs perfusate) in response to noradrenaline (100 nmol; 53.8 +/- 4.0 pmol ml-1 in the presence and 84.8 +/- 8.0 pmol ml-1 in the absence of L-NAME, n = 15, P < 0.05) and carbachol (10 microM; 63.9 +/- 5.0 pmol ml-1 in the presence and 154.0 +/- 9.0 pmol ml-1 in the absence of L-NAME, n = 15, P < 0.05). TRIM (50 microM) did not affect either the vasoconstrictor response to noradrenaline or the vasodilator response to carbachol or the accompanying release of NO from the perfused rat mesentery.

Analgesics↗

PubMed1978

Protection by unsaturated lecithin against the imidazole antimycotics, clotrimazole and miconazole.

The activity of egg lecithin in preventing the antifungal action of the two imidazole antimycotics, clotrimazole and miconazole, was confirmed. However, addition of this phospholipid could not relieve an existing imidazole inhibition. Compared with egg lecithin, reduced egg lecithin showed no such protective effect. The addition of egg lecithin to an aqueous suspension of the imidazole drugs changed the absorption profile of the imidazole, suggesting a low solubility and, consequently, a lower effective concentration; however, the addition of reduced egg lecithin did not produce any change in the adsorption. These results indicate that the preventive effect of egg lecithin on imidazole inhibition may be a consequence of preferential in vitro interaction of the drug with unsaturated phospholipid to form a hydrophobic complex.

Absorption↗

PubMed1981

Effect of imidazole on renal function in unilateral ureteral-obstructed rat kidneys.

Imidazole has been proposed to reverse renal vasoconstriction following unilateral obstruction, presumably through blockade of thromboxane A2 (TXA2) synthesis. We examined this hypothesis in rats subjected to unilateral ureteral obstruction for 24 h by 1) performing renal function studies before and during imidazole infusion, and 2) measuring TXB2 and prostaglandin E2 (PGE2) in urine collected before and during imidazole infusion and the profile of products generated by metabolism of arachidonic acid with renal microsomes in vitro. Imidazole infusion was associated with only a bicarbonaturia in the postobstructed kidney; in contrast, clearance of PAH and inulin, fractional sodium excretion, and bicarbonate excretion were all increased in the contralateral kidney. In the postobstructed and contralateral kidneys, TXB2 excretion was diminished and PGE2 excretion was variable not only following imidazole infusion but after saline infusion as well. The profile of products generated by renal microsomal metabolism of arachidonic acid was similar among obstructed, contralateral, and normal kidneys. These results do not support the proposal that TXA2 is the mediator of renal vasoconstriction following unilateral ureteral obstruction.

Animals↗

PubMed1986

Triiodothyronine repression of imidazole-induced tyrosinase expression in B16 melanoma cells.

Investigations with mouse melanoma B16/C3 cell cultures have suggested that imidazole or a derivative thereof can facilitate expression of the tyrosinase (EC 1.14.18.1) structural gene. The induction of tyrosinase expression by imidazole was inhibited by T3 about 4-fold. When T3 (10 nM) was present for 19 h in proliferating B16/C3 cultures, basal activity of this enzyme was inhibited by approximately 60%. Neither T3 nor imidazole directly affected tyrosinase enzymatic activity in broken cell preparations. Addition of T3 to imidazole-induced cultures rapidly decreased tyrosinase expression (within 30 min) which remained repressed for at least 4 h before recovering. Recovery of tyrosinase activity could be blocked by readdition of hormone. The hormone effect was detectable at 1 nM and was maximal at 10 nM. Removal of supplemental T3 from the medium rapidly reversed the repression of tyrosinase activity. The biologically inactive analog rT3 (10 nM) failed to inhibit basal enzyme activity or alter the imidazole effect on tyrosinase expression. The experimental results with protein and RNA inhibitors indicate that the T3 response is independent of destabilizing the putative transcript for tyrosinase or altering the posttranslational events responsible for its synthesis.

Animals↗

PubMed2002

Temperature and acid-base balance in ectothermic vertebrates: the imidazole alphastat hypotheses and beyond.

The 'imidazole alphastat hypothesis' states that intracellular and extracellular pH, partly via buffering by imidazole groups, change with temperature in a way that keeps imidazole and protein ionization constant, thus maintaining cell function and minimizing shifts of base equivalents and total CO(2), while adjustment of P(CO(2)) involves imidazole-based receptors. 'The hypothesis', which is actually several hypotheses, has been variously perceived and judged, but its underlying conceptual framework remains largely valid, and is reformulated using differential equations requiring less information input than their integral equivalents. Their usefulness is illustrated with published data on temperature responses in fish cells and whole tetrapods. Mathematical modelling allows general principles to be explored with less immediate concern for uncertainties in experimental data and other information. In tetrapods, it suggests that warming is followed by a loss of base equivalents from the body, and that this loss is due to metabolic adjustments that are not part of pH homeostasis. Uncertainties include intracellular buffer values, local variations in P(CO(2)) within the body, the possible role of buffering by bone mineral, and the temperature dependence of pK values for CO(2)/HCO(3)(-) and imidazole groups. The equations utilize a single, notional, temperature-dependent pK value for all non-bicarbonate buffers in a given body compartment. This approximates to the 'passive component' of pH adjustment to temperature change as measured by the homogenate technique. Also discussed are the diversity of cell responses within individual animals, relevant aspects of the control of ventilation, metabolism and transmembrane transport, and the basis of optimum pH-temperature relationships.

Acid-Base Equilibrium↗

PubMed2003

Efficient synthesis of trans- or cis-4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles via diazafulvene intermediates: synthetic approach toward human histamine H4)-ligands.

(+)-4(5)-[(2R,5R)-5-aminomethyltetrahydrofuran-2-yl]imidazole [(+)-1, imifuramine] and its 2R,5S-stereoisomer (+)-2 were expected as base compounds to develop selective human histamine H4-receptor ligands. The improved synthesis of (+)-1 was done via cyclization of a diazafulvene intermediate generated by Bu3P/N,N,N',N'-tetramethylazodicarboxamide (TMAD) treatment of a diol 17ab bearing an unsubstituted imidazole moiety in good yields. This methodology also afforded an alternative synthetic route to trans- and cis-ethyl 4(5)-(5-hydroxymethyltetrahydrofuran-2-yl)imidazole carboxylates (5 and 6), reported previously. Also, 4(5)-[(2R,5S)-5-aminomethyltetrahydrofuran-2-yl]imidazole (+)-2 was synthesized from ethyl 4(5)-(2-deoxy-beta-D-ribofuranosyl)imidazole-1-carboxylate (35) via the four steps involving deoxygenation.

Humans↗

PubMed2004

Artificial neural networks for prediction of antibacterial activity in series of imidazole derivatives.

Artificial neural networks (ANNs) have been applied for the quantitative structure-activity relationships (QSAR) studies of antibacterial activity against Escherichia coli, Serratia marcescens, Proteus vulgaris, Klebsiella pneumoniae and Pseudomonas aeruginosa of a large series of new imidazole derivatives. Antibacterial activity against individual bacteria, expressed as logarithm of reciprocal of the minimal inhibitory concentrations, log 1/MIC, has been related to a number of physicochemical and structural parameters of the imidazole derivatives investigated. Molecular descriptors of agents were obtained by quantum-chemical calculations combined with molecular modelling and from respective structure fragment reference data (e.g., log P). A high correlation resulted between the predicted from ANN model antibacterial activity, log 1/MIC(ANN), and that from biological experiments, log 1/MIC(exp), both for the data used in learning and in the testing sets of imidazoles. Correlation coefficient, R, depending on the type of bacteria and structural subset of analysed imidazole compounds, varies from 0.875 to 0.969. The applicability of ANNs has been demonstrated for the prediction of pharmacological potency of new imidazole derivatives based on their structural descriptors generated exclusively by calculation chemistry.

Anti-Bacterial Agents↗

PubMed1991

Stabilization of the imidazole ring of His-195 at the active site of chloramphenicol acetyltransferase.

The imidazole of His-195 plays an essential role in the proposed general base mechanism of chloramphenicol acetyltransferase (CAT). The structure of the binary complex of CATIII and chloramphenicol suggests that two unusual interactions might determine the conformation of the side chain of His-195: (i) an intraresidue hydrogen bond between its main chain carbonyl and the protonated N delta 1 of the imidazole ring and (ii) face-to-face van der Waals contact between the His-195 imidazole group and the aromatic side chain of Tyr-25. Tyr-25 also makes a hydrogen bond, via its phenolic hydroxyl, to the carbonyl oxygen of the substrate chloramphenicol. Replacement of Tyr-25 of CATIII by phenylalanine results in a modest increase in the Km for chloramphenicol (from 11.6 to 14.6 microM) and a 2-fold fall in kcat (599 to 258 s-1), indicative of a free energy contribution to transition state binding of 0.6 kcal mol-1 for the hydrogen bond between Tyr-25 and chloramphenicol. In contrast, substitution of Tyr-25 by alanine yields an enzyme that is dramatically impaired in its ability to bind chloramphenicol (Km = 173 microM). As kcat for Ala-25 CAT is also reduced (130 s-1), the loss of the aryl group results in a 69-fold decrease in kcat/Km, corresponding to a free energy contribution to binding and catalysis of 2.5 kcal mol-1. In addition to the loss of the hydrogen bond between Tyr-25 and chloramphenicol, the loss of substrate affinity in Ala-25 CAT may be a direct consequence of reduced hydrophobicity of the chloramphenicol-binding site and/or the loss of critical constraints on the precise conformation of the catalytic imidazole. However, as with wild type CAT, inactivation of Ala-25 CAT by the affinity reagent 3-(bromoacetyl) chloramphenicol is accompanied by modification solely at N epsilon 2 of His-195. Hence, the results demonstrate that tautomeric stabilization of the imidazole ring persists in the absence of van der Waals interactions with the side chain of Tyr-25, probably as a consequence of hydrogen bonding between the protonated N delta 1 and the carbonyl oxygen of His-195.

Binding Sites↗

PubMedDate not supplied

Induction and inhibition of rat hepatic drug metabolism by N-substituted imidazole drugs.

Three daily administrations of N-substituted imidazole antimycotics, clotrimazole (CloTZ, 75 mg/kg/day), miconazole (MCZ, 150 mg/kg/day), or tioconazole (TCZ, 150 mg/kg/day), but not the 4,5-disubstituted imidazole cimetidine (350 mg/kg/day) or imidazole (200 mg/kg/day for 4 days), induced rat hepatic cytochrome P-450 and other drug-metabolizing enzymes. These findings paralleled in vitro observations where CloTZ, MCZ, and TCZ were several orders of magnitude more potent as inhibitors of p-nitroanisole O-demethylase activity in control male rat liver microsomes than cimetidine or imidazole. Although no marked difference in inhibitory potency was evident among the N-substituted imidazoles, there were qualitative and quantitative differences in the profiles and extents of induction of various cytochrome P-450-dependent monooxygenases and Phase II conjugation enzymes. Cytochrome P-450 was elevated dramatically by CloTZ (3-4 times the control) and to a lesser extent by MCZ and TCZ (congruent to 1.5 times the control). For all agents, there was an increase in metyrapone binding approximately equivalent to the additional (i.e. above control) cytochrome P-450. Despite the large difference in cytochrome P-450 induction by CloTZ, MCZ, and TCZ, these agents elevated p-nitroanisole demethylase and aniline hydroxylase to similar extents (3-5 X and 1-2 X control, respectively). All agents induced erythromycin and ethylmorphine demethylation in proportion to cytochrome P-450. Ethoxyresorufin O-de-ethylation was not substantially affected by any agent. Large differences in the extent and specificity of induction of microsomal glucuronide conjugations were also evident.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗