Cytochrome P450 (CYP) inhibition screening: Comparison of three tests

Turpeinen, Miia; Korhonen, Laura E.; Tolonen, Ari; Uusitalo, Jouko; Juvonen, Risto O.; Raunio, Hannu; Pelkonen, Olavi

doi:10.1016/j.ejps.2006.06.005

Cited by 52 publications

(38 citation statements)

References 31 publications

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“…Наиболее подходящими для исследования Р450-зависимого метаболизма являются микросомальные или рекомбинантные цитохромы Р450, бакулосомы (клетки насекомых, трансфицированные бакуловирусом и экспрессирующие различные цитохромы Р450), микросомы печени человека [112,113].…”

Section: цитохромы р450unclassified

Sensor systems for medical application based on hemoproteins and nanocomposite materials

et al. 2010

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1 Учреждение Российской академии медицинских наук Научно-исследовательский институт биомедицинской химии имени В.Н. Ореховича РАМН, 119121, Москва, ул. Погодинская, д. 10; факс: 8 (499) Достижения в нанобиотехнологии в последние годы позволили сделать большой прогресс в разработке сенсорных систем на основе нанокомпозитных материалов. В обзоре рассмотрены собственные и литературные данные по наносенсорным системам на основе функционально-значимых для медицины гемопротеинов. Особое внимание уделено электрохимическим нанобиосенсорам и принципам функционирования сенсорных систем медицинского назначения на их основе.Ключевые слова: гемопротеины, электрохимические биосенсоры, нанокомпозитные материалы, каталаза, пероксидаза, цитохром Р450, гемоглобин, миоглобин.ВВЕДЕНИЕ. Одной из задач инженерной (технической) нанотехнологии является сопряжение наноразмерных биообъектов с измерительными аналитическими устройствами. Получение гибридных бионеорганических нанокомпозитных материалов служит "мостом" для такого сопряжения.Функциональная значимость в организме гемопротеинов высока. Участвуя в различных процессах метаболизма живых существ, гемопротеины играют важную роль в поддержании жизни на земле. Гемоглобин и миоглобин осуществляют транспорт молекул кислорода. Цитохром с переносит электроны в митохондриальной дыхательной цепи. Цитохром с оксидаза катализирует реакцию терминального окисления в дыхательной цепи с участием молекулярного кислорода; пероксидаза -окисление органических субстратов пероксидом водорода, а каталаза -разложение самой перекиси. Цитохромы Р450 участвуют в гидроксилировании органических молекул. Синтез оксида азота из L-аргинина катализирует NO-синтаза (рисунок). С химической точки зрения едва ли не всё это многообразие функций основано на окислительно-восстановительных свойствах железа гема [1]. Редокс-активность каталитического центра гемопротеинов и широкий круг катализируемых ими реакций делают гемопротеины перспективными в создании электрохимических биосенсоров. Конструирование платформ для иммобилизации ферментов и детектирования сигнала вовлекает передовые нанотехнологии и наноматериалы, включая нановолокна [2], углеродные нанотрубки [3][4][5] , модификацию поверхности датчиков наночастицами золота [6][7][8][9], пленками полимеров [10][11][12][13][14][15], различными полимерными мембранами [16][17][18][19][20] и т.д. 55 * -адресат для переписки

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Section: цитохромы р450unclassified

Sensor systems for medical application based on hemoproteins and nanocomposite materials

et al. 2010

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“…29,30 Briefly, each incubation mixture contained 0.5 mg of microsomal protein per ml, 0.1 M phosphate buffer (pH 7.4), 1 mM NADPH and all the 10 probe substrates. Substrates, their concentrations and target enzymes for the incubations were melatonin (4 mM, CYP1A2), coumarin (2 mM, CYP2A6), bupropion (1 mM, CYP2B6), amodiaquine (2 mM, CYP2C8), tolbutamide (4 mM, CYP2C9), omeprazole (2 mM, CYP2C19 and CYP3A4), dextromethorphan (0.2 mM, CYP2D6), chlorzoxazone (6 mM, CYP2E1), midazolam (0.4 mM, CYP3A4) and testosterone (1 mM, CYP3A4).…”

Section: Biochemical Assaysmentioning

confidence: 99%

“…Substrate concentrations were close or clearly below the apparent K m values for indicated CYP activities. At these low concentrations 29,30 The CYP2A6 crystal structure with coumarin, methotrexate, 24 N,N-dimethyl(5-(pyridin-3-yl)furan-2-yl)methamine, N-dimethyl(5-(pyridin-3-yl)furan-2-yl)methamine, and dimethyl(5-(pyridin-3-yl)furan-2-yl)methamine 25 and our homology model differed with respect to the amino acid forming a hydrogen bond to the substrate. We therefore generated a new CoMFA model using the coumarin-bound CYP2A6 crystal structure.…”

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confidence: 94%

Identification of inhibitors of the nicotine metabolising CYP2A6 enzyme—an in silico approach

Rahnasto

Wittekindt

et al. 2007

Pharmacogenomics J

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The compulsive nature of tobacco use is attributable to nicotine addiction. Nicotine is eliminated by metabolism through the cytochrome P450 2A6 (CYP2A6) enzyme in liver. Inhibition of CYP2A6 by chemical compounds may represent a potential supplement to anti-smoking therapy. The purpose of this study was to rationally design potent inhibitors of CYP2A6. 3D-QSAR models were constructed to find out which structural characteristics are important for inhibition potency. Specifically located hydrophobic and hydrogen donor features were found to affect inhibition potency. These features were used in virtual screening of over 60 000 compounds in the Maybridge chemical database. A total of 22 candidate molecules were selected and tested for inhibition potency. Four of these were potent and selective CYP2A6 inhibitors with IC 50 values lower than 1 mM. They represent novel structures of CYP2A6 inhibitors, especially N1-(4-fluorophenyl)cyclopropane-1-carboxamide. This compound can be used as a lead in the design of CYP2A6 inhibitor drugs to combat nicotine addiction.

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“…51,52 Quinidine, a potent inhibitor of CYP2D6, was used as the control compound to determine intra-and inter-assay variability. Stock solutions (1 mM) of CMT, DEX, MA, and MDMA were each prepared in HPLC-grade acetonitrile before each CYP2D6 assay.…”

Section: Inhibition Studies Purified Cyp2d6mentioning

confidence: 99%

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Wallace¹,

Crosswy²

2017

Toxicol Forensic Med Open J

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Citation ResearchAbSTRACT Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug-drug interactions, leading to increased drug toxicity. Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H 2 -antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC 50 ) of each drug. Kinetic analysis (V max and K m ) was accomplished using rodent hepatic microsomes. Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated V max elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/ min). The K m was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [V max ; 280-490%] and affinity [K m ; 165-220%] values compared to the control group. The increase in both V max and K m suggests that the low affinity/high capacity CYP2D2 isoform is upregulated. Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity.

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Cytochrome P450 (CYP) inhibition screening: Comparison of three tests

Cited by 52 publications

References 31 publications

Sensor systems for medical application based on hemoproteins and nanocomposite materials

Sensor systems for medical application based on hemoproteins and nanocomposite materials

Identification of inhibitors of the nicotine metabolising CYP2A6 enzyme—an in silico approach

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

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