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https://www.readbyqxmd.com/read/29469947/evaluation-of-the-metabolic-capability-of-primary-human-hepatocytes-in-three-dimensional-cultures-on-microstructural-plates
#1
Satoshi Koyama, Hiroshi Arakawa, Manabu Itoh, Norio Masuda, Kentaro Yano, Hajime Kojima, Takuo Ogihara
The NanoCulture Plate (NCP) is a novel microstructural plate designed as a base for the three-dimensional culture of cells/tissues. Here, we examined whether or not the metabolic capability of human primary hepatocytes is well maintained during culture on NCPs. The hepatocytes formed aggregates after seeding and their ATP content was well maintained during culture for 21 days. Expression of CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 mRNAs was detected throughout the 21-day culture period. Addition of CYP substrate drugs (midazolam, diclofenac, lamotrigine and acetaminophen) resulted in the formation of multiple metabolites with a corresponding decrease in the amounts of the unchanged compounds...
February 22, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29468688/polymorphisms-of-cytochrome-p450-2b6-cyp2b6-in-cynomolgus-and-rhesus-macaques
#2
Yasuhiro Uno, Shotaro Uehara, Hiroshi Yamazaki
BACKGROUND: Cytochrome P450 2B6 (CYP2B6) is an important drug-metabolizing enzyme and is expressed in liver. Although human CYP2B6 variants account for variable enzyme properties among individuals and populations, CYP2B6 genetic variants have not been investigated in cynomolgus macaques, widely used in drug metabolism studies. METHODS: CYP2B6 was resequenced in 120 cynomolgus macaques and 23 rhesus macaques by direct sequencing. RESULTS: Twenty-three non-synonymous variants were found, of which 12 and 3 were unique to cynomolgus macaques and rhesus macaques, respectively...
February 22, 2018: Journal of Medical Primatology
https://www.readbyqxmd.com/read/29430676/metabolite-identification-of-the-antimalarial-naphthoquine-using-liquid-chromatography-tandem-high-resolution-mass-spectrometry-in-combination-with-multiple-data-mining-tools
#3
Yanhong Sun, Shuqi Wang, Jianbo Ji, Guangxi Zhai, Jie Xing
Naphthoquine (NQ) is one of important partner drugs of Artemisinin-based combination therapy (ACT), which is recommended for the treatment of uncomplicated Plasmodium falciparum. NQ shows a high cure rate after a single oral administration. It is absorbed quickly (Tmax 2-4 h) and has a long elimination half-life (255 h). However, the metabolism of NQ has not been clarified. In this work, the metabolite profiling of NQ was studied in six liver microsomal incubates (human, cynomolgus monkey, beagle dog, mini pig, rat and CD1 mouse), seven recombinant CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and rat (plasma, urine, bile and feces ) using liquid chromatography tandem high-resolution LTQ-Orbitrap mass spectrometry (HRMSn ) in conjunction with online H/D exchange...
February 12, 2018: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/29417863/marmoset-cytochrome-p450-2b6-a-propofol-hydroxylase-expressed-in-liver
#4
Toru Oshio, Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
1. The common marmoset (Callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. Cytochrome P450 (P450) 2B enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available. 2. Marmoset P450 2B6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. Phylogenetic analysis using amino acid sequences indicated that marmoset P450 2B6 was closer to human and cynomolgus monkey P450 2B6 than to P450 2B orthologs of other species, including pigs, dogs, rabbits, and rodents...
February 8, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29414024/metabolism-of-flavonolignans-in-human-hepatocytes
#5
Jiří Vrba, Barbora Papoušková, Lenka Roubalová, Martina Zatloukalová, David Biedermann, Vladimír Křen, Kateřina Valentová, Jitka Ulrichová, Jan Vacek
This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29402634/a-cyp2b6-humanized-mouse-model-and-its-potential-applications
#6
REVIEW
Lei Li, Qing-Yu Zhang, Xinxin Ding
CYP2B6 is a human microsomal cytochrome P450 enzyme with broad substrate selectivity. CYP2B6 is the only functional member of the human CYP2B gene subfamily, which differs from the situation in rodents, such as mouse, where multiple functional Cyp2b genes are expressed. Recent studies with Cyp2b knockout or knockdown mouse models have yielded insights into the in vivo roles of mouse CYP2B enzymes in drug disposition and xenobiotic toxicity. A CYP2B6-humanized mouse model (CYP2A13/2B6/2F1-transgenic/Cyp2abfgs-null), which expresses human CYP2B6 in the liver, and human CYP2A13 and CYP2F1 in the respiratory tract, but not any of the mouse Cyp2b genes, has also been established...
January 11, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29330218/a-study-on-pharmacokinetics-of-bosentan-with-systems-modeling-part-1-translating-systemic-plasma-concentration-to-liver-exposure-in-healthy-subjects
#7
Rui Li, Mark Niosi, Nathaniel Johnson, David A Tess, Emi Kimoto, Jian Lin, Xin Yang, Keith A Riccardi, Sangwoo Ryu, Ayman F El-Kattan, Tristan S Maurer, Larry M Tremaine, Li Di
Understanding liver exposure of hepatic transporter substrates in clinical studies is often critical as it typically governs pharmacodynamics, drug-drug interactions, and toxicity for certain drugs. However, this is a challenging task since there is currently no easy method to directly measure drug concentration in the human liver. Using bosentan as an example, a new approach has been demonstrated to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically-based pharmacokinetic modeling...
January 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29329342/ternary-copper-ii-complex-nci60-screening-toxicity-studies-and-evaluation-of-efficacy-in-xenograft-models-of-nasopharyngeal-carcinoma
#8
Munirah Ahmad, Shazlan-Noor Suhaimi, Tai-Lin Chu, Norazlin Abdul Aziz, Noor-Kaslina Mohd Kornain, D S Samiulla, Kwok-Wai Lo, Chew-Hee Ng, Alan Soo-Beng Khoo
Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4...
2018: PloS One
https://www.readbyqxmd.com/read/29302220/a-brief-review-of-the-genetics-and-pharmacogenetics-of-opioid-use-disorders
#9
Wade Berrettini
Increased physician prescribing of opioids to treat chronic nonprogressive pain has been accompanied by an increase in opioid addiction. Twin studies of opioid addiction are consistent with an inherited component of risk, approximately 50%. Several genome-wide association study (GWAS) reports indicate that genetic risk for opioid addiction is conveyed by many alleles of small effect (odds ratios <1.5). These reports have detected alleles in potassium-ion-channel genes (KCNC1 and KCNG2) and in a glutamate receptor auxiliary protein (CNIH3)...
September 2017: Dialogues in Clinical Neuroscience
https://www.readbyqxmd.com/read/29205871/pharmacogenetic-analysis-of-the-model-based-pharmacokinetics-of-five-anti-hiv-drugs-how-does-this-influence-the-effect-of-aging
#10
Jingxian Chen, Farida S Akhtari, Michael J Wagner, Oscar Suzuki, Tim Wiltshire, Alison A Motsinger-Reif, Julie B Dumond
Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV-infected patients. Seventy-four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging-PGx-PK association and interaction analyses were conducted using one-way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P-glycoprotein (P-gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants...
December 3, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/29176019/in-vitro-modulation-of-the-cytochrome-p450-and-abcb1-p-glycoprotein-activities-of-the-aqueous-extract-of-allophylus-cominia-l-sw-leaves
#11
Carlos L Pérez, Maria T Donato, Ivones Hernández, Miriam T Paz Lopes, Evangelina Marrero, Jose A Herrera, Maria J Gómez-Lechón, Idania Rodeiro
BACKGROUND: The aqueous extract of the Allophylus cominia (L) Sw (Sapindaceae) leaves has shown anti-diabetic, anti-obesity and anti-inflammatory properties. In the Caribbean region, it is typically used for the treatment of type-2 diabetes. METHODS: Considering the herb-drug interaction, the aim of this study was to evaluate the potential effects of the A. cominia extract on the cytochrome P450 (CYP) (rat hepatocyte model) and P-glycoprotein (P-gp) (4T1 cell line) systems...
November 25, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29121650/flavin-containing-monooxygenase-3-fmo3-role-in-busulphan-metabolic-pathway
#12
Ibrahim El-Serafi, Ylva Terelius, Manuchehr Abedi-Valugerdi, Seán Naughton, Maryam Saghafian, Ali Moshfegh, Jonas Mattsson, Zuzana Potácová, Moustapha Hassan
Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood...
2017: PloS One
https://www.readbyqxmd.com/read/29120380/in-vitro-phase-i-metabolism-of-crv431-a-novel-oral-drug-candidate-for-chronic-hepatitis-b
#13
Daniel J Trepanier, Daren R Ure, Robert T Foster
The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0-80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species...
November 9, 2017: Pharmaceutics
https://www.readbyqxmd.com/read/29081796/hepatocyte-cyp2b6-can-be-expressed-in-cell-culture-systems-by-exerting-physiological-levels-of-shear-implications-for-adme-testing
#14
REVIEW
Timothy G Hammond, Holly H Birdsall
Cytochrome 2B6 (CYP2B6) has substantial clinical effects on morbidity and mortality and its effects on drug metabolism should be part of hepatotoxicity screening. Examples of CYP2B6's impacts include its linkage to mortality during cyclophosphamide therapy and its role in determining hepatotoxicity and CNS toxicity during efavirenz therapy for HIV infection. CYP2B6 is key to metabolism of many common drugs from opioids to antidepressants, anesthetics, and anticonvulsants. But CYP2B6 has been extremely difficult to express in cell culture, and as a result, it has been largely deemphasized in preclinical toxicity studies...
2017: Journal of Toxicology
https://www.readbyqxmd.com/read/29054967/prediction-of-cytochrome-p450-mediated-drug-clearance-in-humans-based-on-the-measured-activities-of-selected-cyps
#15
Jie Gao, Jie Wang, Na Gao, Xin Tian, Jun Zhou, Yan Fang, Hai-Feng Zhang, Qiang Wen, Lin-Jing Jia, Dan Zou, Hai-Ling Qiao
Determining drug-metabolizing enzyme activities on an individual basis is an important component of personalized medicine, and cytochrome P450 enzymes (CYPs) play a principal role in hepatic drug metabolism. Herein, a simple method for predicting the major CYP-mediated drug clearance in vitro and in vivo is presented. Ten CYP-mediated drug metabolic activities in human liver microsomes (HLMs) from 105 normal liver samples were determined. The descriptive models for predicting the activities of these CYPs in HLMs were developed solely on the basis of the measured activities of a smaller number of more readily assayed CYPs...
October 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29018344/xanthates-as-useful-probes-for-testing-the-active-sites-of-cytochromes-p450-4a11-and-2e1
#16
Tsveta Stoyanova, Iglika Lessigiarska, Momir Mikov, Ilza Pajeva, Stanislav Yanev
Xanthates (alkyl or aryl derivatives of dithiocarbonic acid) have been shown to be selective mechanism-based inactivators of cytochromes P450 2B1/2B6 and 2E1 due to covalent binding of a reactive intermediate to apoprotein after double hydrogen abstraction at α-carbon atom, suggesting interaction of the xanthate dithiocarbonic head with the enzyme heme. The structures of xanthates with a long alkyl chain are similar to the fatty acids. Saturated fatty acids (FA) such as lauric acid (LA), are metabolized by different cytochrome P450 isoforms to ω- and (ω-1)-hydroxy products, in humans done by CYP4A11 and CYP2E1, respectively...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28994497/effects-of-vernonia-cinerea-compounds-on-drug-metabolizing-cytochrome-p450s-in-human-liver-microsomes
#17
Phisit Pouyfung, Songklod Sarapusit, Pornpimol Rongnoparut
Vernonia cinerea has been widely used in traditional medicines for various diseases and shown to aid in smoking abstinence and has anticancer properties. V. cinerea bioactive compounds, including flavonoids and hirsutinolide-type sesquiterpene lactones, have shown an inhibition effect on the nicotine-metabolizing cytochrome P450 2A6 (CYP2A6) enzyme and hirsutinolides reported suppressing cancer growth. In this study, V. cinerea ethanol extract and its bioactive compounds, including four flavonoids and four hirsutinolides, were investigated for an inhibitory effect on human liver microsomal CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 using cocktail inhibition assays combined with LC-MS/MS analysis...
October 10, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28962520/editor-s-highlight-complete-attenuation-of-mouse-lung-cell-proliferation-and-tumorigenicity-in-cyp2f2-knockout-and-cyp2f1-humanized-mice-exposed-to-inhaled-styrene-for-up-to-2%C3%A2-years-supports-a-lack-of-human-relevance
#18
George Cruzan, James S Bus, Marcy I Banton, Satinder S Sarang, Robbie Waites, Debra B Layko, James Raymond, Darol Dodd, Melvin E Andersen
Styrene is a mouse-specific lung carcinogen, and short-term mode of action studies have demonstrated that cytotoxicity and/or cell proliferation, and genomic changes are dependent on CYP2F2 metabolism. The current study examined histopathology, cell proliferation, and genomic changes in CD-1, C57BL/6 (WT), CYP2F2(-/-) (KO), and CYP2F2(-/-) (CYP2F1, 2B6, 2A13-transgene) (TG; humanized) mice following exposure for up to 104 weeks to 0- or 120-ppm styrene vapor. Five mice per treatment group were sacrificed at 1, 26, 52, and 78 weeks...
October 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28951217/assessing-molecular-initiating-events-mies-key-events-kes-and-modulating-factors-mfs-for-styrene-responses-in-mouse-lungs-using-whole-genome-gene-expression-profiling-following-1-day-and-multi-week-exposures
#19
Melvin E Andersen, George Cruzan, Michael B Black, Salil N Pendse, Darol Dodd, James S Bus, Satinder S Sarang, Marcy I Banton, Robbie Waites, Patrick D McMullen
Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 strain, a CYP2F2(-/-) knock out and a CYP2F2(-/-) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm...
November 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28934153/inhibitory-effect-of-selaginellins-from-selaginella-tamariscina-beauv-spring-against-cytochrome-p450-and-uridine-5-diphosphoglucuronosyltransferase-isoforms-on-human-liver-microsomes
#20
Jae-Kyung Heo, Phi-Hung Nguyen, Won Cheol Kim, Nguyen Minh Phuc, Kwang-Hyeon Liu
Selaginella tamariscina (Beauv.) has been used for traditional herbal medicine for treatment of cancer, hepatitis, and diabetes in the Orient. Numerous bioactive compounds including alkaloids, flavonoids, lignans, and selaginellins have been identified in this medicinal plant. Among them, selaginellins having a quinone methide unit and an alkylphenol moiety have been known to possess anticancer, antidiabetic, and neuroprotective activity. Although there have been studies on the biological activities of selaginellins, their modulatory potential of cytochrome P450 (P450) and uridine 5'-diphosphoglucuronosyltransferase (UGT) activities have not been previously evaluated...
September 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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