Inter-individual variability in drug response is a major clinical problem. Much of the variability has been observed in drug metabolism, particularly in the enzymes of cytochrome P450. Genetic polymorphism in these enzymes may influence a patient's response to commonly prescribed drugs. The first part of this review describes the enzymatic system of cytochrome P450 and further focuses on the influence of genetic polymorphism of cytochrome P450 1A2 on drug effect.

• MeSH
• biotransformace genetika   MeSH
• cytochrom P-450 CYP1A2 genetika   MeSH
• farmakogenetika * MeSH
• léčivé přípravky metabolismus   MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• systém (enzymů) cytochromů P-450 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• cytochrom P-450 CYP1A2 MeSH
• léčivé přípravky MeSH
• systém (enzymů) cytochromů P-450 MeSH

The anticancer drug ellipticine exerts its genotoxic effects after metabolic activation by cytochrome P450 (CYP) enzymes. The present study has examined the role of cytochrome P450 oxidoreductase (POR) and cytochrome b5 (Cyb5), electron donors to P450 enzymes, in the CYP-mediated metabolism and disposition of ellipticine in vivo. We used Hepatic Reductase Null (HRN) and Hepatic Cytochrome b5/P450 Reductase Null (HBRN) mice. HRN mice have POR deleted specifically in hepatocytes; HBRN mice also have Cyb5 deleted in the liver. Mice were treated once with 10 mg/kg body weight ellipticine (n = 4/group) for 24 h. Ellipticine-DNA adduct levels measured by 32P-postlabelling were significantly lower in HRN and HBRN livers than in wild-type (WT) livers; however no significant difference was observed between HRN and HBRN livers. Ellipticine-DNA adduct formation in WT, HRN and HBRN livers correlated with Cyp1a and Cyp3a enzyme activities measured in hepatic microsomes in the presence of NADPH confirming the importance of P450 enzymes in the bioactivation of ellipticine in vivo. Hepatic microsomal fractions were also utilised in incubations with ellipticine and DNA in the presence of NADPH, cofactor for POR, and NADH, cofactor for Cyb5 reductase (Cyb5R), to examine ellipticine-DNA adduct formation. With NADPH adduct formation decreased as electron donors were lost which correlated with the formation of the reactive metabolites 12- and 13-hydroxy-ellipticine in hepatic microsomes. No difference in adduct formation was observed in the presence of NADH. Our study demonstrates that Cyb5 contributes to the P450-mediated bioactivation of ellipticine in vitro, but not in vivo.

• Klíčová slova
• Cytochrome P450, Cytochrome b(5), DNA Adducts, Metabolism, Mouse models,
• MeSH
• adukty DNA metabolismus   MeSH
• antitumorózní látky metabolismus   farmakologie   MeSH
• aromatické hydroxylasy metabolismus   MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom-B(5)-reduktasa nedostatek   genetika   MeSH
• cytochromy b5 nedostatek   genetika   MeSH
• elipticiny metabolismus   farmakologie   MeSH
• fenotyp MeSH
• genotyp MeSH
• hepatocyty enzymologie   MeSH
• jaterní mikrozomy enzymologie   MeSH
• játra enzymologie   MeSH
• metabolická aktivace MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• NADPH-cytochrom c-reduktasa metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• antitumorózní látky MeSH
• aromatické hydroxylasy MeSH
• CYP3A protein, mouse MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom-B(5)-reduktasa MeSH
• cytochromy b5 MeSH
• elipticiny MeSH
• ellipticine MeSH Prohlížeč
• NADPH-cytochrom c-reduktasa MeSH
• systém (enzymů) cytochromů P-450 MeSH

The enzymes of cytochrome P450 3A subfamily are responsible for the metabolism of about 50% of commonly used drugs. High inter-individual variability in the activities of these enzymes has been described. The last fourth part of this review focuses on the influence of genetic polymorphism of CYP3A4 and CYP3A5 enzymes on drug effect.

• MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• CYP3A4 protein, human MeSH Prohlížeč
• CYP3A5 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH

Silybin (a flavonolignan, the main component of silymarin, an extract from the seeds of Silybum marianum) has been used to date mostly as a hepatoprotectant. However, it also has other interesting activities, e.g., anticancer and hypocholesterolemic effects. It is also known that silybin can inhibit the activities of the cytochrome P450 (P450) enzymes. In this study, a weak interaction of silybin with human microsomal CYP2E1, 2A6, 2B6, 2C19, and 2D6 (IC(50) > or = 250 microM) was found; a moderate inhibition was observed for CYP1A2 and 2C8. The most prominent inhibition effect was found with CYP3A4 and CYP2C9 (IC(50) < or = 50 microM). Using mass spectometry detection, production of O-demethylated (the main metabolite) as well as hydroxylated derivatives of silybin formed by P450 enzymes was detected. The effect of different P450 inhibitors on the formation of O-demethylated product was also studied. In particular, a relatively specific inhibitor of CYP2C8 (quercetin) markedly inhibited the formation of this metabolite. With the help of recombinant enzymes (bactosomes), it was confirmed that the CYP2C8 enzyme is responsible for the reaction leading to O-demethylated silybin.

• MeSH
• antioxidancia metabolismus   farmakologie   MeSH
• aromatické hydroxylasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2C8 MeSH
• cytochrom P450 CYP2C9 MeSH
• Escherichia coli genetika   metabolismus   MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 MeSH
• inhibitory enzymů metabolismus   farmakologie   MeSH
• jaterní mikrozomy účinky léků   enzymologie   metabolismus   MeSH
• katalýza účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• oxid uhelnatý farmakologie   MeSH
• quercetin farmakologie   MeSH
• rekombinantní proteiny metabolismus   MeSH
• silibinin MeSH
• silymarin chemie   metabolismus   farmakologie   MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• aromatické hydroxylasy MeSH
• CYP1A2 protein, human MeSH Prohlížeč
• CYP2C8 protein, human MeSH Prohlížeč
• CYP2C9 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2C8 MeSH
• cytochrom P450 CYP2C9 MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 MeSH
• inhibitory enzymů MeSH
• oxid uhelnatý MeSH
• quercetin MeSH
• rekombinantní proteiny MeSH
• silibinin MeSH
• silymarin MeSH
• systém (enzymů) cytochromů P-450 MeSH

Cytochrome P450 (P450) 2U1 has been shown to be expressed, at the mRNA level, in human thymus, brain, and several other tissues. Recombinant P450 2U1 was purified and used as a reagent in a metabolomic search for substrates in bovine brain. In addition to fatty acid oxidation reactions, an oxidation of endogenous N-arachidonoylserotonin was characterized. Subsequent NMR and mass spectrometry and chemical synthesis showed that the main product was the result of C-2 oxidation of the indole ring, in contrast to other human P450s that generated different products. N-Arachidonoylserotonin, first synthesized chemically and described as an inhibitor of fatty acid amide hydrolase, had previously been found in porcine and mouse intestine; we demonstrated its presence in bovine and human brain samples. The product (2-oxo) was 4-fold less active than N-arachidonoylserotonin in inhibiting fatty acid amide hydrolase. The rate of oxidation of N-arachidonoylserotonin was similar to that of arachidonic acid, one of the previously identified fatty acid substrates of P450 2U1. The demonstration of the oxidation of N-arachidonoylserotonin by P450 2U1 suggests a possible role in human brain and possibly other sites.

• Klíčová slova
• Arachidonic Acid, Cytochrome P450, Eicosanoid, Lipid Oxidation, Mass Spectrometry (MS),
• MeSH
• chromatografie kapalinová MeSH
• erytrocyty enzymologie   MeSH
• Escherichia coli metabolismus   MeSH
• hmotnostní spektrometrie MeSH
• indoly metabolismus   MeSH
• játra enzymologie   MeSH
• katalýza MeSH
• kyseliny arachidonové metabolismus   MeSH
• kyslík metabolismus   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární sekvence - údaje MeSH
• mozek metabolismus   MeSH
• polymerázová řetězová reakce MeSH
• proteomika MeSH
• regulace genové exprese enzymů MeSH
• rodina 2 cytochromů P450 MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• serotonin analogy a deriváty   metabolismus   MeSH
• skot MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• arachidonoylserotonin MeSH Prohlížeč
• CYP2U1 protein, human MeSH Prohlížeč
• indoly MeSH
• kyseliny arachidonové MeSH
• kyslík MeSH
• rodina 2 cytochromů P450 MeSH
• serotonin MeSH
• systém (enzymů) cytochromů P-450 MeSH

The market share of single-enantiomer drugs is steadily increasing. The pharmacodynamics and pharmacokinetics of individual enantiomers can differ considerably. Thus, their characteristics have to be addressed as early as possible in the development process of new pharmaceuticals. Capillary electrophoresis is a promising technique for enantioselective drug metabolism studies due to highly effective separations, minuscule consumption of sample and reagents, compatibility with a variety of detection techniques, high-throughput via automation, and the implementation of online procedures. An online method comprised of the diffusion-based mixing of cytochrome P450 3A4 with racemic ketamine, incubation of the enzyme reaction, separation of the reaction products S- and R-norketamine, and their quantification is presented in this chapter. Since diffusion is an inherent property of all molecules, the method enables the addition of virtually any compound to the reaction mixture without the need for additional optimization of the mixing conditions, and thus can be favorably used for the rapid screening of putative cytochrome P450 3A4 inhibitors.

• Klíčová slova
• Capillary electrophoresis, Cytochrome P450 3A4, Drug metabolism, Enantioselective separation, Enzyme inhibition, In-capillary reactor, Ketamine, Transverse diffusion of laminar flow profiles,
• MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• elektroforéza kapilární metody   MeSH
• inhibitory cytochromu P450 CYP3A farmakologie   MeSH
• ketamin analogy a deriváty   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• plošný screening metody   MeSH
• stereoizomerie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytochrom P-450 CYP3A MeSH
• inhibitory cytochromu P450 CYP3A MeSH
• ketamin MeSH
• norketamine MeSH Prohlížeč

OBJECTIVE: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. METHODS: We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions. RESULTS: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

• MeSH
• játra metabolismus   MeSH
• kanabinoidy metabolismus   MeSH
• lidé MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• kanabinoidy MeSH
• systém (enzymů) cytochromů P-450 MeSH

The vast majority of approved drugs are metabolized by the five major cytochrome P450 (CYP) isozymes, 1A2, 2C9, 2C19, 2D6 and 3A4. Inhibition of CYP isozymes can cause drug-drug interactions with severe pharmacological and toxicological consequences. Computational methods for the fast and reliable prediction of the inhibition of CYP isozymes by small molecules are therefore of high interest and relevance to pharmaceutical companies and a host of other industries, including the cosmetics and agrochemical industries. Today, a large number of machine learning models for predicting the inhibition of the major CYP isozymes by small molecules are available. With this work we aim to go beyond the coverage of existing models, by combining data from several major public and proprietary sources. More specifically, we used up to 18815 compounds with measured bioactivities to train random forest classification models for the individual CYP isozymes. A major advantage of the new data collection over existing ones is the better representation of the minority class, the CYP inhibitors. With the new data collection we achieved inhibitor-to-non-inhibitor ratios in the order of 1:1 (CYP1A2) to 1:3 (CYP2D6). We show that our models reach competitive performance on external data, with Matthews correlation coefficients (MCCs) ranging from 0.62 (CYP2C19) to 0.70 (CYP2D6), and areas under the receiver operating characteristic curve (AUCs) between 0.89 (CYP2C19) and 0.92 (CYPs 2D6 and 3A4). Importantly, the models show a high level of robustness, reflected in a good predictivity also for compounds that are structurally dissimilar to the compounds represented in the training data. The best models presented in this work are freely accessible for academic research via a web service.

• Klíčová slova
• Cytochrome P450 inhibition, Drug metabolism, Machine learning, Metabolism prediction,
• MeSH
• inhibitory cytochromu P450 chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• strojové učení * MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory cytochromu P450 MeSH
• systém (enzymů) cytochromů P-450 MeSH

Amphetamine-based drugs, including methamphetamine, are some of the most widely used illegal drugs in the world. Methamphetamine is metabolized by the cytochrome P450s, the latter also being involved in the metabolism of many drugs and other xenobiotics. The effect of methamphetamine pretreatment (10 mg kg-1, intraperitoneally once daily for 6 days) on the activity of the P450 enzymes was assessed both in the rat isolated perfused liver and in vivo. The rate of 4-hydroxydiclofenac production was significantly enhanced in vivo, indicating a possible stimulatory effect on P4502C6. Similarly, the kinetics of tolbutamide and dextromethorphan in isolated perfused rat liver indicate a significant increase in both P4502C6 and the P4502D subfamily. No significant changes in midazolam kinetic in the isolated perfused rat liver were observed. The potential for methamphetamine to cause drug interactions is of clinical relevance and, therefore, it warrants further investigation. Until further drug interaction experiments are accomplished, the co-administration of drugs with methamphetamine should be conducted with caution.

• MeSH
• antagonisté excitačních aminokyselin farmakokinetika   MeSH
• dextromethorfan farmakokinetika   MeSH
• diklofenak analogy a deriváty   metabolismus   MeSH
• hypnotika a sedativa farmakokinetika   MeSH
• hypoglykemika farmakokinetika   MeSH
• játra enzymologie   MeSH
• kinetika MeSH
• krysa rodu Rattus MeSH
• methamfetamin farmakokinetika   MeSH
• midazolam farmakokinetika   MeSH
• perfuze MeSH
• potkani Wistar MeSH
• rodina 2 cytochromů P450 MeSH
• steroid-21-hydroxylasa metabolismus   MeSH
• stimulanty centrálního nervového systému farmakokinetika   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• techniky in vitro MeSH
• tolbutamid farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4'-hydroxydiclofenac MeSH Prohlížeč
• antagonisté excitačních aminokyselin MeSH
• Cyp2c6v1 protein, rat MeSH Prohlížeč
• dextromethorfan MeSH
• diklofenak MeSH
• hypnotika a sedativa MeSH
• hypoglykemika MeSH
• methamfetamin MeSH
• midazolam MeSH
• rodina 2 cytochromů P450 MeSH
• steroid-21-hydroxylasa MeSH
• stimulanty centrálního nervového systému MeSH
• systém (enzymů) cytochromů P-450 MeSH
• tolbutamid MeSH

The majority of human P450 dependent drug metabolism is carried out by polymorphic enzymes which can alter plasma concentration of the pharmacological active substance followed by an enhanced or suppressed pharmacological effect. The response of individual patients to drugs can be affected by variations in DNA sequence mainly by single nucleotide polymorphisms (SNPs). Knowledge of functionally important SNPs prior to the drug administrations may assist in the development of individualized pharmacotherapy avoiding unexpected drug responses, such as harmful adverse drug reactions or treatment failures. This review discusses both the basic characteristics of the major polymorphic cytochrome P450 enzymes and examines the pharmacogenetic methods employed to estimate metabolic status. We will focus mainly on the basic principles of genotyping assays involving molecular biology tools.

• MeSH
• aromatické hydroxylasy genetika   MeSH
• cytochrom P-450 CYP2D6 genetika   MeSH
• cytochrom P450 CYP2C19 MeSH
• fenotyp MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• oxygenasy se smíšenou funkcí genetika   MeSH
• polymorfismus genetický * MeSH
• polymorfismus konformace jednovláknové DNA MeSH
• systém (enzymů) cytochromů P-450 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• aromatické hydroxylasy MeSH
• CYP2C19 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP2D6 MeSH
• cytochrom P450 CYP2C19 MeSH
• oxygenasy se smíšenou funkcí MeSH
• systém (enzymů) cytochromů P-450 MeSH