Phenotype Analysis of Human Cytochrome P450 2C9 Polymorphism Using a Panel of Fluorine-Substituted Benzo[h]quinolines as Inhibitors of Tolbutamide Hydroxylation

Matsuyama, Noriko; Kato, Takaaki; Kimura, Kazunori; Mizutani, Takaharu; Saeki, Ken-ichi

doi:10.1248/jhs.52.821

Cited by 8 publications

(25 citation statements)

References 10 publications

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“…It was reported that the inhibition of CYP2C9 by BhQ and its fluorinated derivatives varied with the position of the substituted fluorine (11). The effects of fluorine substitution on the inhibition of TB hydroxylation catalyzed by CYP2C9*1 were different compared with the effects on the hydroxylation catalyzed by CYP2C9*2 and CYP2C9*3 (11). Additionally, fluorine substitution in quinoline and 4-methylquinoline affected their mutagenicity and the formation of hydroxylated metabolites (18,19).…”

Section: Resultsmentioning

confidence: 99%

“…The determination of TB hydroxylase activity catalyzed by CYP2C9 was performed according to previous reports with slight modifications (11,14). Briefly, the incubation mixture (50 µL in a 1.5-mL microtube) contained 0.1 M potassium phosphate buffer (pH 7.4), 1.3 mM NADP, 3.3 mM G6P, 3.3 mM MgCl 2 , 0.08 units of G6P dehydrogenase, TB, or 3'-F-TB, and 5.0 pmol CYP (approximately 8 µg protein).…”

Section: Determination Of Cyp2c9 Activity By Tb Hydroxylationmentioning

confidence: 99%

“…Fluorine substitution of a hydrogen atom often exerts so-called mimic effects on interactions with biological molecules because the covalent and van der Waals' radii of the fluorine atom are similar to those of the hydrogen atom (11). However, the replacement of hydrogen with fluorine changes not only the distribution of electron density within the molecule but also the electric repulsive/attractive interactions with intra/intermolecular environments, which may significantly affect enzymesubstrate and enzyme-inhibitor interactions.…”

Section: Introductionmentioning

confidence: 99%

“…However, the replacement of hydrogen with fluorine changes not only the distribution of electron density within the molecule but also the electric repulsive/attractive interactions with intra/intermolecular environments, which may significantly affect enzymesubstrate and enzyme-inhibitor interactions. In our previous study, the inhibitory effects of fluorinated benzo[h]quinolines (BhQ) on drug metabolism by recombinant human CYP2C9 were analyzed, and the position-specific substitution by a fluorine atom was shown to alter the ability of BhQ to inhibit CYP2C9 (11). The present study aimed to determine whether fluorine substitution improves the decrease in metabolic activity catalyzed by CYP2C9 polymorphic isozymes.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic analysis of human CYP2C9 polymorphisms using fluorine-substituted tolbutamide

Kitamura

Saeki

2020

DD&T

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To investigate the effect of fluorine substitution on tolbutamide (TB) hydroxylation catalyzed by CYP2C9, the hydroxylation of TB and its fluorinated derivative 3'-fluoro-tolbutamide (3'-F-TB) by recombinant human CYP2C9*1, CYP2C9*2, and CYP2C9*3 was analyzed. In general, fluorine substitution near the metabolic site may decrease enzymatic oxidation owing to its electron-withdrawing nature. Fluorine substitution reduced the Michaelis-Menten-derived K m of 4'-hydroxylation of TB catalyzed by CYP2C9*1 from 115 (TB) to 77 (3'-F-TB) µM. In the case of TB hydroxylation catalyzed by CYP2C9*2, the K m value of TB was also reduced by fluorine substitution from 129 to 88 µM. The greatest effect of fluorine substitution on the K m in TB hydroxylation was observed in the catalysis by CYP2C9*3, in which the K m value decreased from 287 to 117 µM. When a mixture containing TB and 3′-F-TB was hydroxylated by CYP2C9, the hydroxylated metabolite ratio in CYP2C9*3 was significantly increased compared with that in CYP2C9*1 and CYP2C9*2 (p < 0.01, Tukey-Kramer test). These results suggest that obtaining the metabolite profiles of fluorine-substituted analogs of the key substrate molecule may be useful as a new tool for phenotyping polymorphic CYP isoforms.

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Section: Resultsmentioning

confidence: 99%

Section: Determination Of Cyp2c9 Activity By Tb Hydroxylationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phenotypic analysis of human CYP2C9 polymorphisms using fluorine-substituted tolbutamide

Kitamura

Saeki

2020

DD&T

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“…1 The substances can also have a variety of biological activities. 2 As such, the aza-polycyclic aromatic compounds have been the frequent targets of synthetic methods. 3 Our own superacid-promoted reactions gave aza-polycyclic aromatic compounds by reactions involving dicationic intermediates (Eq.…”

Section: Introductionmentioning

confidence: 99%

Ring closing and opening reactions leading to aza-polycyclic aromatic compounds

Kethe

Klumpp

2012

Tetrahedron

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Hantzsch‐Like Synthesis, DNA Photocleavage, DNA/BSA Binding, and Molecular Docking Studies of Bis(sulfanediyl)bis(tetrahydro‐5‐deazaflavin) Analogs Linked to Naphthalene Core

Ragheb

Abdelwahab

Darweesh

et al. 2022

Chemistry & Biodiversity

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The cyclocondensation reaction of aldehydes with dimedone and bis(6-aminopyrimidin-4-one) in acetic acid led to the formation of the corresponding bis (pyrimido[4,5-b]quinoline-4,6-diones) which are known as bis(sulfanediyl)bis(tetrahydro-5-deazaflavin) analogs in a single step. Also, bis(pyrimido[4,quinoline-4,6diones) which are linked to naphthyl core via phenoxymethyl linkage is prepared. The interactions of the synthesized compounds with DNA and bovine serum albumin (BSA) were studied. Gel electrophoresis assay was used to show the capability of the compounds to photocleave the supercoiled pBR322 plasmid DNA in UV-A (365 nm). Besides, the most photocleavable compound, bis(tetrahydropyrimido[4,5-b]quinoline-4,6-dione) linked to pyridin-3-yl at position-5 exhibits good binding affinities toward CT-DNA and BSA as supported by UV/VIS spectral studies. In addition to the experimental findings, a molecular docking simulation was performed to collect detailed binding data for this compound to both biomolecules.

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Phenotype Analysis of Human Cytochrome P450 2C9 Polymorphism Using a Panel of Fluorine-Substituted Benzo[h]quinolines as Inhibitors of Tolbutamide Hydroxylation

Abstract: To investigate the inhibitory effect of aza-polycyclic aromatic compounds on cytochrome P450 (CYP)2C9

Cited by 8 publications

References 10 publications

Phenotypic analysis of human CYP2C9 polymorphisms using fluorine-substituted tolbutamide

Phenotypic analysis of human CYP2C9 polymorphisms using fluorine-substituted tolbutamide

Ring closing and opening reactions leading to aza-polycyclic aromatic compounds

Hantzsch‐Like Synthesis, DNA Photocleavage, DNA/BSA Binding, and Molecular Docking Studies of Bis(sulfanediyl)bis(tetrahydro‐5‐deazaflavin) Analogs Linked to Naphthalene Core

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