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https://www.readbyqxmd.com/read/29793051/promising-antileishmanial-activity-of-novel-imidazole-antifungal-drug-luliconazole-against-leishmania-major-in-vitro-and-in-silico-studies
#1
Azar Shokri, Mahdi Abastabar, Masoud Keighobadi, Saeed Emami, Mahdi Fakhar, Saeed Hosseini Teshnizi, Koichi Makimura, Ali Rezaei-Matehkolaei, Hassan Mirzaei
OBJECTIVES: Pentavalent antimonials have been used for the treatment of leishmaniasis for more than 70 years; however their toxicity limits their benefits. Unfortunately, the efficacy of the first line drugs has been decreased and resistance seems to be noticeable. Luliconazole is a new azole with unique effects on fungi which has not been tested on Leishmania parasites yet. METHODS: In the present study, we evaluated cytotoxicity and anti-leishmanial activities of Luliconazole on promastigotes and intracellular amastigotes of Leishmania major (L...
May 21, 2018: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/29792946/investigation-of-nonalcoholic-fatty-liver-disease-induced-drug-metabolism-by-comparative-global-toxicoproteomics
#2
Ann-Yae Na, Jung Jae Jo, Ok Kwang Kwon, Riya Shrestha, Piljoung Cho, Kyu Min Kim, Sung Hwan Ki, Tae Hee Lee, Tae Won Jeon, Tae Cheon Jeong, Sangkyu Lee
Non-alcoholic fatty liver disease (NAFLD) includes conditions such as steatosis, non-alcoholic steatohepatitis, and ultimately hepatocellular carcinoma. Although the pathology of NAFLD is well-established, NAFLD-induced drug metabolism mediated by cytochrome P450 (CYP) in the liver has remained largely unexplored. Therefore, we investigated NAFLD-induced drug metabolism mediated by CYP by quantitative toxicoproteomics analysis. After administration of a methionine-choline deficient (MCD) diet to induce development of NAFLD, tandem mass tags-based liquid chromatography-tandem mass spectrometry analysis was conducted to investigate the dynamics of hepatic proteins...
May 21, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29792703/structure-based-design-of-inhibitors-with-improved-selectivity-for-steroidogenic-cytochrome-p450-17a1-over-cytochrome-p450-21a2
#3
Charlie Fehl, Caleb D Vogt, Rahul Yadav, Kelin Li, Emily E Scott, Jeffrey Aubé
Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site...
May 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29792573/inherent-resistance-to-14%C3%AE-demethylation-inhibitor-fungicides-in-colletotrichum-truncatum-is-likely-linked-to-cyp51a-and-or-cyp51b-gene-variants
#4
Shuning Chen, Yunyun Wang, Guido Schnabel, Congyue Annie Peng, Satyanarayana Lagishetty, Kerry Smith, Chao-Xi Luo, Huizhu Yuan
Anthracnose disease, caused by Colletotrichum truncatum, affects marketable yield during preharvest production and postharvest storage of fruits and vegetables worldwide. Demethylation inhibitor fungicides (DMIs) are among the very few chemical classes of single-site mode of action fungicides that are effective in controlling anthracnose disease. However, some species are inherently resistant to DMIs and more information is needed to understand this phenomenon. Isolates of C. truncatum were collected from the USA and China from peach, soybean, citrus, and begonia and sensitivity to six DMIs (difenoconazole, propiconazole, metconazole, tebuconazole, flutriafol and fenbuconazole) was determined...
May 24, 2018: Phytopathology
https://www.readbyqxmd.com/read/29791008/the-pharmacology-pharmacokinetics-efficacy-and-adverse-events-associated-with-kava
#5
REVIEW
C Michael White
Kava is a plant with numerous kavapyrones that can induce pharmacologic effects and drug interactions through the cytochrome P450 and P-glycoprotein systems. Kava is used recreationally and for the treatment of anxiety. Clinical trials verify anxiolytic effects in excess of placebo, but the effects are not seen immediately and the optimal dose and dosing schedule needs to be determined. Clinical trials usually lasting for 4 weeks found generally good tolerability and safety; however, dermatologic, hepatologic, and cognitive adverse effects may occur...
May 23, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29790944/the-reducing-clade-iib-polyketide-synthase-pks14-acts-as-a-virulence-determinant-of-the-entomopathogenic-fungus-beauveria-bassiana
#6
Chettida Srisuksam, Juntira Punya, Songsak Wattanachaisaereekul, Wachiraporn Toopaang, Supapon Cheevadhanarak, Morakot Tanticharoen, Alongkorn Amnuaykanjanasin
pks14, a reducing clade IIb polyketide synthase gene, is preserved throughout the evolution of entomopathogenic fungi. We examined the functions of pks14 in Beauveria bassiana using targeted gene disruption. pks14 disruption was verified by Southern blot and PCR analyses. The radial growth, cell dry weight and conidial germination of Δpks14 were comparable to that of the wild type. Our sequence and gene expression analyses of the pks14 biosynthetic cluster demonstrated: (i) cotranscription and constitutive expression of nearly all genes of the aforementioned cluster including C2H2 zinc finger transcription regulator gene, but not pks14 and cytochrome P450 gene; (ii) expression of pks14 gene in insect-containing culture condition only; whereby (iii) a KAR9-like gene in direct proximity with pks14 is the only gene showing co-regulation...
May 22, 2018: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/29790809/characterization-of-in-vitro-and-in-vivo-metabolism-of-leelamine-using-liquid-chromatography-tandem-mass-spectrometry
#7
Riya Shrestha, Jung Jae Jo, DooHyun Lee, Taeho Lee, Sangkyu Lee
1. Leelamine is a diterpene compound found in the bark of pine trees and has garnered considerable interest owing to its potent anticancer properties. The aim of the present study was to investigate the metabolic profile of leelamine in human liver microsomes (HLMs) and mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 2. We found that leelamine undergoes only Phase I metabolism, which generates one metabolite that is mono-hydroxylated at the C9 carbon of the octahydrophenanthrene ring (M1) both in vitro and in vivo...
May 23, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29790354/-opioids-and-new-trends-in-pain-therapy
#8
Jan Lejčko
Opioids are well known for their ability to reduce the perception of pain without a loss of consciousness. However, the influence of opioids on organism is very complex. Clinical pharmacology of currently available opioid analgesics is determined by three major factors - their opioid receptor properties, pharmacokinetic properties and genetic polymorphism in the opiate receptor and cytochrome P450 isoform. In acute severe pain are opioids very efficient. Long-term experience with opioid analgesia in patients with cancer pain has shown high favorable risk/benefit ratio...
2018: Casopís Lékar̆ů C̆eských
https://www.readbyqxmd.com/read/29789925/associations-of-polymorphisms-of-cyp2d6-and-cyp2c9-with-early-onset-severe-pre-eclampsia-and-response-to-labetalol-therapy
#9
Cheng-Juan Sun, Lin Li, Xue-Yan Li, Wei-Yuan Zhang, Xiao-Wei Liu
PURPOSE: Early onset preeclampsia (PPE) contributes to life-threatening maternal complications and fetal demise. Pharmacogenomics is a precision medicine, and metabolizing enzymes responsive to antihypertensive remains understudied. The aim of this study was to evaluate the associations of polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with PPE and the relationship among CYP2D6, CYP2C9 polymorphisms and response to labetalol therapy...
May 22, 2018: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/29788543/a-new-glutathione-conjugate-of-the-pyrrolizidine-alkaloids-produced-by-human-cytosolic-enzyme-dependent-reactions-in-vitro
#10
Fashe Muluneh, Merja R Häkkinen, Rami El-Dairi, Markku Pasanen, Risto O Juvonen
RATIONALE: The toxic metabolites of pyrrolizidine alkaloids (PAs) are initially formed by cytochrome P450 mediated oxidation reactions and primarily eliminated as glutathione (GSH) conjugates. Although the reaction between the reactive metabolites and GSH can occur spontaneously, the role of the cytosolic enzymes in the process has not been studied. METHODS: The toxic metabolites of selected PAs (retrorsine, monocrotaline, senecionine, lasiocarpine, heliotrine or senkirkine) were generated by incubating them in 100 mM phosphate buffer pH 7...
May 22, 2018: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/29788535/cyp2a5-promoter-based-gene-reporter-assay-a-novel-design-of-cell-based-bioassay-for-toxicity-prediction
#11
A'edah Abu-Bakar, Hao Hu, Matti A Lang
The murine cytochrome P450 2a5 (Cyp2a5) gene is regulated by complex interactions of various stress-activated transcription factors (TFs). Elevated Cyp2a5 transcription under chemical-induced stress conditions is achieved by interplay between the various TFs-including as aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2)-at the "stress-responding" cluster of response elements on the Cyp2a5 promoter, as well as through mRNA stabilisation mediated by interaction of the stress-activated heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) with the 3'UTR of the CYP2A5 mRNA...
May 22, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29785610/evaluation-of-strategies-for-the-assessment-of-drug-drug-interactions-involving-cytochrome-p450-enzymes
#12
Jelle Reinen, Martijn Smit, Mira Wenker
BACKGROUND AND OBJECTIVES: Drug-drug interactions (DDIs) can occur when one drug alters the metabolism of another drug. Drug metabolism mediated by cytochrome P450 enzymes (CYPs) is responsible for the majority of metabolism of known drugs and inhibition of CYP enzymes is a well-known cause of DDIs. In the current study, the use of various human liver microsomes (HLM)-based methods to determine occurrence of CYP-mediated metabolism-dependent inhibition (MDI) and possible follow-up studies were evaluated...
May 21, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29785500/boosting-the-efficiency-of-site-saturation-mutagenesis-for-a-difficult-to-randomize-gene-by-a-two-step-pcr-strategy
#13
Aitao Li, Carlos G Acevedo-Rocha, Manfred T Reetz
Site-saturation mutagenesis (SSM) has been used in directed evolution of proteins for a long time. As a special form of saturation mutagenesis, it involves individual randomization at a given residue with formation of all 19 amino acids. To date, the most efficient embodiment of SSM is a one-step PCR-based approach using NNK codon degeneracy. However, in the case of difficult-to-randomize genes, SSM may not deliver all of the expected 19 mutants, which compels the user to invest further efforts by applying site-directed mutagenesis for the construction of the missing mutants...
May 21, 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29785355/identification-and-expression-analysis-of-cytokinin-metabolic-genes-ipts-cyp735a-and-ckxs-in-the-biofuel-plant-jatropha-curcas
#14
Li Cai, Lu Zhang, Qiantang Fu, Zeng-Fu Xu
The seed oil of Jatropha curcas is considered a potential bioenergy source that could replace fossil fuels. However, the seed yield of Jatropha is low and has yet to be improved. We previously reported that exogenous cytokinin treatment increased the seed yield of Jatropha . Cytokinin levels are directly regulated by isopentenyl transferase (IPT), cytochrome P450 monooxygenase, family 735, subfamily A (CYP735A), and cytokinin oxidase/dehydrogenase (CKX). In this study, we cloned six IPT genes, one JcCYP735A gene, and seven JcCKX genes...
2018: PeerJ
https://www.readbyqxmd.com/read/29784972/comprehensive-analysis-of-the-mouse-cytochrome-p450-family-responsible-for-omega-3-epoxidation-of-eicosapentaenoic-acid
#15
Yosuke Isobe, Mai Itagaki, Yuko Ito, Satoko Naoe, Kotoe Kojima, Mitsunori Ikeguchi, Makoto Arita
Metabolites generated via oxygenation of the omega-3 double bond (omega-3 oxygenation) in eicosapentaenoic acid (EPA) have recently been identified as novel anti-inflammatory lipid mediators. Therefore, oxygenase(s) responsible for this metabolic pathway are of particular interest. We performed genome-wide screening of mouse cytochrome P450 (CYP) isoforms to explore enzymes involved in omega-3 oxygenation of EPA. As a result, 5 CYP isoforms (mouse Cyp1a2, 2c50, 4a12a, 4a12b, and 4f18) were selected and identified to confer omega-3 epoxidation of EPA to yield 17,18-epoxyeicosatetraenoic acid (17,18-EpETE)...
May 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29784821/characterization-of-gossypol-biosynthetic-pathway
#16
Xiu Tian, Ju-Xin Ruan, Jin-Quan Huang, Chang-Qing Yang, Xin Fang, Zhi-Wen Chen, Hui Hong, Ling-Jian Wang, Ying-Bo Mao, Shan Lu, Tian-Zhen Zhang, Xiao-Ya Chen
Gossypol and related sesquiterpene aldehydes in cotton function as defense compounds but are antinutritional in cottonseed products. By transcriptome comparison and coexpression analyses, we identified 146 candidates linked to gossypol biosynthesis. Analysis of metabolites accumulated in plants subjected to virus-induced gene silencing (VIGS) led to the identification of four enzymes and their supposed substrates. In vitro enzymatic assay and reconstitution in tobacco leaves elucidated a series of oxidative reactions of the gossypol biosynthesis pathway...
May 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29784381/synthesis-of-a-selective-ratiometric-fluorescent-probe-based-on-naphthalimide-and-its-application-in-human-cytochrome-p450-1a
#17
Xiuxuan Zhang, Yan Zhou, Xiaofei Gu, Yu Cheng, Manxin Hong, Liqiang Yan, Fulong Ma, Zhengjian Qi
Cytochrome P450s have brought considerable attention to researchers for their significant correlations with metabolic behaviors of procarcinogenic chemicals. To better understand the roles of CYP1A in biological and physiological systems, we developed a novel ratiometric fluorescence probe N-((2-hydroxyl ethoxy) ethyl)- 4-methoxy-1, 8-naphthalimide (NEMN) allowing for selectively and sensitively monitoring the target enzymes under physiological conditions and living cells. The probe was designed based on substrate predilection of CYP1A and its outstanding O-dealkylation capacity, and 1, 8-naphthalimide was chosen as fluorophore on account of its desirable photophysical properties...
August 15, 2018: Talanta
https://www.readbyqxmd.com/read/29782898/incorporation-of-absorption-and-metabolism-into-liver-toxicity-prediction-for-phytochemicals-a-tiered-in-silico-qsar-approach
#18
Yitong Liu
An increased use of herbal dietary supplements has been associated with adverse liver effects such as elevated serum enzymes and liver failure. The safety assessment for herbal dietary supplements is challenging since they often contain complex mixtures of phytochemicals, most of which have unknown pharmacokinetic and toxicological properties. Rapid tools are needed to evaluate large numbers of phytochemicals for potential liver toxicity. The current study demonstrates a tiered approach combining identification of phytochemicals in liver toxic botanicals, followed by in silico quantitative structure-activity relationship (QSAR) evaluation of these phytochemicals for absorption (e...
May 18, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29781479/substrate-mediated-redox-partner-selectivity-of-cytochrome-p450
#19
Katherine A Gentry, Meng Zhang, Sang-Choul Im, Lucy Waskell, Ayyalusamy Ramamoorthy
Investigating the interplay between cytochrome-P450 and its redox partners (CPR and cytochrome-b5) is vital for understanding the metabolism of most hydrophobic drugs. Dynamic structural interactions with the ternary complex, with and without substrates, captured by NMR reveal a gating mechanism for redox partners to promote P450 function.
May 21, 2018: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/29780235/the-cytochrome-p450-isoenzyme-and-some-new-opportunities-for-the-prediction-of-negative-drug-interaction-in-vivo
#20
REVIEW
Dmitrij A Sychev, Ghulam Md Ashraf, Andrey A Svistunov, Maksim L Maksimov, Vadim V Tarasov, Vladimir N Chubarev, Vitalij A Otdelenov, Natal'ja P Denisenko, George E Barreto, Gjumrakch Aliev
Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction...
2018: Drug Design, Development and Therapy
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