Inhibition of human CYP1A2 activity<i>in vitro</i>by methylxanthines: potent competitive inhibition by 8-phenyltheophylline

Murray, Stephen A.; Odupitan, A. O. A.; Murray, B. P.; Boobis, Alan R.; Edwards, R. J.

doi:10.1080/00498250110043292

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…P450 1A2 is highly inducable by exposure to polycyclic aromatic hydrocarbons, such as some present in cigarette smoke, charcoal grilled meat, diet containing compounds as indole derivatives, and some therapeutic drugs as omeprazole (87). Its active site is able to accommodate planar molecules of moderate volume and basicity [5,9]. Prominent inhibitors include some selective serotonin reuptake inhibitors and antiarrhythmics [10].…”

Section: P450 1a2mentioning

confidence: 99%

“…Of the two non-substrates -haloperidol (7) and verapamil (19) -included in the test set, haloperidol (7) was wrongly assessed active. Of the P450 1A2 substrates, five tricyclic structures and mexiletine (9) were not included in the hitlist. A visual inspection of these false negative results showed that the tricyclic structures map perfectly the RA and the H feature; however, the HBA feature is not mapped.…”

Section: Ligand-based General Model For P450 1a2 Substratesmentioning

confidence: 99%

“…They may alternatively have additional interaction sites with the enzyme which are not covered by our model. For very small (1) phenacetin (2) amitriptyline (3) clozapine (4) cyclobenzaprine (5) estradiol (6) haloperidol (7) imipramine (8) mexiletine (9) naproxen (10) olanzapine (11) ondansetron (12) propranolol (13) riluzole (14) ropivacaine (15) tacrine (16) theophylline (17) tizanidine (18) compounds like mexiletine (9), it might not be necessary to occupy all three interaction spheres to be recognized and metabolized by P450 1A2.…”

Section: Ligand-based General Model For P450 1a2 Substratesmentioning

confidence: 99%

“…To examine which features of a compound may facilitate its ability to competitively occupy the active site of P450 1A2, a first model was generated based on three potent, chemically diverse inhibitors: α-naphthoflavone (23), acacetin (24), and fluvoxamine (25) ( Table 3) [9,[65][66][67][68][69]. The hypothesis generation process returned ten models of which the best ranked was most suitable for describing structural requirements for P450 1A2 inhibition.…”

Section: Ligand-based General Model For Competitive P450 1a2 Inhibitorsmentioning

confidence: 99%

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Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

Schuster

Laggner²,

Steindl³

et al. 2006

CDDT

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In today's drug discovery process, the very early consideration of ADME properties is aimed at a reduction of drug candidate drop out rate in later development stages. Apart from in vitro testing, in silico methods are evaluated as complementary screening tools for compounds with unfavorable ADME attributes. Especially members of the cytochrome P450 (P450) enzyme superfamily-- e.g. P450 1A2, P450 2C9, P450 2C19, P450 2D6, and P450 3A4-- contribute to xenobiotic metabolism, and compound interaction with one of these enzymes is therefore critically evaluated. Pharmacophore models are widely used to identify common features amongst ligands for any target. In this study, both structure-based and ligand-based models for prominent drug-metabolizing members of the P450 family were generated employing the software packages LigandScout and Catalyst. Essential chemical ligand features for substrate and inhibitor activity for all five P450 enzymes investigated were determined and analyzed. Finally, a collection of 11 pharmacophores for substrates and inhibitors was evaluated as an in silico P450 profiling tool that could be used for early ADME estimation of new chemical entities.

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Section: P450 1a2mentioning

confidence: 99%

Section: Ligand-based General Model For P450 1a2 Substratesmentioning

confidence: 99%

Section: Ligand-based General Model For P450 1a2 Substratesmentioning

confidence: 99%

Section: Ligand-based General Model For Competitive P450 1a2 Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

Schuster

Laggner²,

Steindl³

et al. 2006

CDDT

View full text Add to dashboard Cite

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“…CYP1A2, like CYP3A4, catalyzes the metabolism of neutral/basic, lipophilic, or planar molecules with at least one hydrogen-bonding site, making both the furanocoumarin monomers and dimers candidates for an interaction with this enzyme. In addition to the compounds tested, flavonoids (Zhai et al, 1998;Murray et al, 2001), methylxanthines (Murray et al, 2001), grapefruit juice, 6Ј,7Ј-dihydroxybergamottin, bergamottin, and the naturally occurring dimers GF-I-1 and GF-I-4 (Tassaneeyakul et al, 2000) have been shown to be potent to moderate inhibitors of CYP1A2 activity, using phenacetin as the marker substrate. The increased selectivity of the 55EE analog suggests different orientations for the 5-and 8-substituted ring systems within the binding domains for CYP1A2 and CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

Development of Novel Furanocoumarin Dimers as Potent and Selective Inhibitors of Cyp3a4

Row

Brown²,

Stachulski³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Grapefruit juice has been found to cause an increase in the oral bioavailability of many therapeutic agents. Such interactions are believed to result from the mechanism-based inhibition of CYP3A4 activity in the intestine. Furanocoumarin dimers present in the juice have been found to be extremely potent inhibitors of CYP3A4 activity. The aim of this work was to synthesize and test a series of dimers with a view to defining the relationship between structure and inhibitory activity and establish whether they might make suitable probes of CYP3A4 activity. Eleven furanocoumarin dimers were synthesized and evaluated as inhibitors of CYP3A4 using human liver microsomes, with testosterone as the marker substrate. Four of the most potent dimers were also investigated for their effects on CYP3A4 activity in the human intestine and on five additional hepatic cytochrome P450 isoforms. The dimers showed In conclusion, all the dimers tested were extremely potent inhibitors of CYP3A4 activity. In particular, dimer 55EE was highly selective toward the enzyme, suggesting that this compound is a suitable probe for determining the contribution of CYP3A4 to drug metabolism.There has been substantial interest in the inhibition of CYP3A4 activity by the constituents of grapefruit juice. This effect was first recognized by Bailey et al. (1989) from a chance finding in a felodipine-ethanol interaction study in which grapefruit juice was used to mask the taste of the alcohol. Elevated plasma felodipine concentrations were observed both in the alcohol and control phases of the study, and in a later study, grapefruit juice was found to triple the mean area under the plasma concentration-time curve through inhibition of CYP3A4 . Subsequently, a large number of studies have been performed on the effects of grapefruit juice on a range of drugs of therapeutic importance, such as terfenadine (Benton et al., 1996;Rau et al., 1997) , 1995). The constituents of grapefruit juice that cause inhibition of CYP3A4 have not been conclusively identified. Strong candidates are the furanocoumarins, particularly the bergamottin series (Ohnishi et al., 2000;Kakar et al., 2004). However, there is no clear evidence that any one compound is primarily responsible, and it is possible that the interaction arises from the accumulative effect of a number of constituents present in the juice. Of the compounds isolated, three dimers, namely, GF-I-1, GF-I-4, and GF-I-6 (Fig. 1), possibly derived from the geranyloxy monomer (6Ј,7Ј-dihydroxybergamottin), were the most potent inhibitors of CYP3A4 activity (Fukuda et al., 1997;Guo et al., 2000a;Tassaneeyakul et al., 2000). Potencies were found to exceed that of ketoconazole and were shown to be 1 to 2 orders of magnitude higher than those observed for the monomers bergamottin, 6Ј,7Ј-epoxybergamottin, and 6Ј,7Ј-dihydroxybergamottin, when using testosterone as the marker substrate (Guo et al., 2000b).Inhibition of CYP3A4 activity by grapefruit juice is believed to be the result of mechanism-based inactivation (S...

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The analysis of methylxanthine fractions obtained from Camellia sinensis cultivated in Turkey and effects on the in vitro inhibition of CYP2D6 enzyme

Attar

Yapaöz

2022

Biotech and App Biochem

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Tea is a worldwide consumed herbal beverage and it was aimed in this study to reveal the major fractions of green and black tea in order to enlighten the in vitro inhibition potency on the well-known drug metabolizing enzyme CYP2D6 activity. Methylxanthine fractions were extracted from green and black tea and a yield of 0.265 g (1.06%) for 25 g of dried black tea and 0.302 g (1.2%) for 25 g of green tea was calculated. High-performance liquid chromatography analysis represented that the major components of the methylxanthine fractions were caffeine, theobromine, and theophylline. Methylxanthine content of black tea was 368.25 ± 4.6 μg/ml caffeine, 89.30 ± 2.3 μg/ml theobromine, and 3.40 ± 0.5 μg/ml theophylline, whereas that of green tea was 176.50 ± 3.7 μg/ml caffeine, 53.85 ± 1.4 μg/ml theobromine, and 2.06 ± 0.7 μg/ml theophylline. The results of concentration-dependent inhibition studies were 76% green tea, 75% black tea, and 55% caffeine at concentration of 10 mg/ml. The inhibition rates of green and black tea on CYP2D6 activity were 76% and 75%, respectively, where that of quinidine, the well-known inhibitor of CYP2D6, was 82%. Our results indicate that green and black tea is very likely to modify the CYP2D6 enzyme activity.

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Inhibition of human CYP1A2 activityin vitroby methylxanthines: potent competitive inhibition by 8-phenyltheophylline

Cited by 11 publications

References 29 publications

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

Development of Novel Furanocoumarin Dimers as Potent and Selective Inhibitors of Cyp3a4

The analysis of methylxanthine fractions obtained from Camellia sinensis cultivated in Turkey and effects on the in vitro inhibition of CYP2D6 enzyme

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