Structure-activity relationships in the effects of 1-alkylimidazoles on microsomal oxidation in vitro and in vivo

Wilkinson, C.F.; Hetnarski, Krystyna; Cantwell, G.Patricia; Carlo, Frederick J. Di

doi:10.1016/0006-2952(74)90227-5

Cited by 174 publications

(36 citation statements)

References 11 publications

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“…The striking differences observed among the phenylimidazoles used in this study appear to depend on the tautomeric imidazole structure and the position of chlorine, whereas the flexibility of BEI appears to be decisive in inducing conformational strain on the binding pocket. The largest unfa- There are observed discrepancies between the K D and IC 50 values for several nitrogenous heterocycles, suggesting that the type II spectral changes may not constitute good indicators of inhibitory potency (47)(48)(49). In this study, 1-BI showed a higher spectral K D values compared with 4-CPI, although its IC 50 values were 2-fold lower than those of 4-CPI.…”

Section: Discussionmentioning

confidence: 44%

Conformational Flexibility of Mammalian Cytochrome P450 2B4 in Binding Imidazole Inhibitors with Different Ring Chemistry and Side Chains

Muralidhara

Negi

Chin

et al. 2006

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 44%

Conformational Flexibility of Mammalian Cytochrome P450 2B4 in Binding Imidazole Inhibitors with Different Ring Chemistry and Side Chains

Muralidhara

Negi

Chin

et al. 2006

Journal of Biological Chemistry

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“…Primaquine appears to inhibit EE2 2-hydroxylation non-competitively. 1-Methylimidazole, a potent inhibitor of aldrin epoxidation in vitro (Wilkinson & Hetnarski, 1974), had a relatively high IC50.…”

Section: Discussionmentioning

confidence: 99%

The metabolism of 17 alpha‐ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.

Purba

Maggs

Orme

et al. 1987

Brit J Clinical Pharma

105

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1 The metabolism of 17ot-ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2 2-Hydroxyethinyloestradiol (2-OHEE2) was either the sole or principal metabolite. Small amounts of 6-hydroxyethinyloestradiol and 16-hydroxyethinyloestradiol were produced by some of the livers.3 EE2 (10 /M) underwent substantial (5-20% of incubated drug), though highly variable, NADPH-dependent metabolism to material irreversibly bound to microsomal protein. 4 2-OHEE2 appeared to be the pro-reactive metabolite.5 The maximum EE2 2-hydroxylase activity was 0.67 nmol min-1 mg-' microsomal protein, with a Km value of 8.6 FLM. 6 Oestradiol, which is mainly hydroxylated to 2-hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. 7 Progesterone, which undergoes 2-hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. 8 Primaquine was the most potent non-steroidal inhibitor but was non-competitive. Other non-steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2-hydroxylation. 9 The results of this study suggest that EE2 2-hydroxylation is metabolised by a form(s) of cytochrome P-450 which has affinity for endogenous steroids.

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“…3B). Ketoconazole, a broad spectrum antifungal drug, is known to specifically inhibit cytochrome P-450 mixed-function oxidases by interacting with the heme iron of the cytochrome (42). Ketoconazole is also known to inhibit 25(OH)D3 la-hydroxylase activity in renal mitochondria (43).…”

Section: Identificationmentioning

confidence: 99%

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

Proc. Natl. Acad. Sci. U.S.A.

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In vitro studies were performed to assess the ability of hepatic homogenates, mitochondria, and microsomes to la-hydroxylate 25-hydroxyvitamin D3 (25(OH)D3]. Addition of 25(OH)D3 to either hepatic mitochondria or microsomes caused a concentration-dependent increase in the production of 1,25-dihydroxyvitamin D3 [1,25(OH) Because of its inability to achieve substrate saturation, meaningful kinetic parameters could not be calculated for the hepatic microsomal la-hydroxylase. These data demonstrate the liver to be an even more dynamic organ than was previously believed with respect to vitamin D metabolism in that the liver has the potential to produce 1,25(OH)2D3 in situ by at least two separate mechanisms.It is well established that various side chain and/or A-ring hydroxylation reactions are essential for the metabolic activation of vitamin D3 (1, 2). Circulating vitamin D3 first undergoes a hepatic conversion to 25-hydroxyvitamin D3 [25(OH)D3] (3). The hydroxylase enzymes responsible for this conversion are known to be cytochrome P-450 mixed-function oxidases that are NADPH dependent and are located in both hepatic mitochondria (4-6) and microsomes (7,8). Final activation of 25(OH)D3 into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] takes place primarily in the kidney (9). The renal enzyme responsible for this activation, 25(OH)D3 lahydroxylase, is also known to be a cytochrome P450 mixedfunction oxidase that is located solely in the inner mitochondrial membrane (10, 11). In recent years, other tissues have also been shown to be capable of synthesizing 1,25(OH)2D3, including placenta (12), bone cells (13), lymphatic tissue (14), and keratinocytes (15). Compared with the renal 25(OH)D3 la-hydroxylase, very little information is known with respect to the metabolic control of these extrarenal 25(OH)D3 lahydroxylases and essentially no information is available concerning their subcellular distribution.Because of the important role of 1,25(OH)2D3 in various aspects of hepatic function (16-24), the possibility that the liver could synthesize in situ this hormonal form of vitamin D3 was investigated. It is reported here that both hepatic mitochondria and microsomes possess a 25(OH)D3 lahydroxylase in significant amounts. These enzymes differ in some characteristics, but both appear to behave as cytochrome P-450 mixed-function oxidases. MN). Coomassie blue protein assay reagent was purchased from Pierce. Nicotinamide adenine dinucleotide phosphate, isocitrate, N,N'-diphenylethylenediamine (DPED), dithiothreitol, and ethylenediaminetetraacetic acid were purchased from Sigma. All solvents were of HPLC grade and were obtained from Fisher. MATERIALS AND METHODS ReagentsLivers. Livers from 3-month-old castrated male pigs, maintained on stock diet, were obtained at the time of slaughter. The livers were perfused with ice-cold 0.15 M NaCl, minced, and placed in an appropriate volume of ice-cold 50 mM Na2HPO4 (pH 7.4) buffer containing 0.25 M sucrose and 0.5 mM EDTA to provide a 20% (wt/vol) 6009The publication costs of th...

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Structure-activity relationships in the effects of 1-alkylimidazoles on microsomal oxidation in vitro and in vivo

Cited by 174 publications

References 11 publications

Conformational Flexibility of Mammalian Cytochrome P450 2B4 in Binding Imidazole Inhibitors with Different Ring Chemistry and Side Chains

Conformational Flexibility of Mammalian Cytochrome P450 2B4 in Binding Imidazole Inhibitors with Different Ring Chemistry and Side Chains

The metabolism of 17 alpha‐ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

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