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Aparajita Banerjee, Björn Hamberger
Catalyzing stereo- and regio-specific oxidation of inert hydrocarbon backbones, and a range of more exotic reactions inherently difficult in formal chemical synthesis, cytochromes P450 (P450s) offer outstanding potential for biotechnological engineering. Plants and their dazzling diversity of specialized metabolites have emerged as rich repository for functional P450s with the advances of deep transcriptomics and genome wide discovery. P450s are of outstanding interest for understanding chemical diversification throughout evolution, for gaining mechanistic insights through the study of their structure-function relationship, and for exploitation in Synthetic Biology...
2018: Phytochemistry Reviews: Proceedings of the Phytochemical Society of Europe
Jianxiu Yao, Yu Cheng Zhu, John Adamczyk, Randall Luttrell
Acephate (organophosphate) is frequently used to control piercing/sucking insects in field crops in southern United States, which may pose a risk to honey bees. In this study, toxicity of acephate (formulation Bracket® 97) was examined in honey bees through feeding treatments with sublethal (pollen residue level: 0.168 mg/L) and median-lethal (LC50 : 6.97 mg/L) concentrations. Results indicated that adult bees treated with acephate at residue concentration did not show significant increase in mortality, but esterase activity was significantly suppressed...
March 18, 2018: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Monica Serra, Michela Marongiu, Antonella Contini, Toshio Miki, Erika Cadoni, Ezio Laconi, Fabio Marongiu
Amniotic epithelial cells (AECs) represent a useful and noncontroversial source for liver-based regenerative medicine, as they can differentiate into hepatocytes upon transplantation into the liver. However, the possibility that AECs can differentiate into other liver cell types, such as hepatic sinusoidal endothelial cells (HSECs), has never been assessed. In order to test this hypothesis, rat- and human-derived AECs (rAECs and hAECs, respectively) were subjected to endothelial cell tube formation assay in vitro...
January 2018: Cell Transplantation
Ayyappa Kumar Sista Kameshwar, Wensheng Qin
To understand the common gene expression patterns employed by P. placenta during lignocellulose degradation, we have retrieved genome wide transcriptome datasets from NCBI GEO database and analyzed using customized analysis pipeline. We have retrieved the top differentially expressed genes and compared the common significant genes among two different growth conditions. Genes encoding for cellulolytic (GH1, GH3, GH5, GH12, GH16, GH45) and hemicellulolytic (GH10, GH27, GH31, GH35, GH47, GH51, GH55, GH78, GH95) glycoside hydrolase classes were commonly up regulated among all the datasets...
2018: International Journal of Biological Sciences
Leabaneng Tawe, Thato Motshoge, Pleasure Ramatlho, Naledi Mutukwa, Charles Waithaka Muthoga, Ghyslaine Bruna Djeunang Dongho, Axel Martinelli, Elias Peloewetse, Gianluca Russo, Isaac Kweku Quaye, Giacomo Maria Paganotti
Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499)...
March 20, 2018: Scientific Reports
Melissa L Sykes, Vicky M Avery
Using high throughput, high-content imaging, a proprietary library was screened against intracellular Trypanosoma cruzi amastigotes to identify compounds with novel activity against the parasite. Five inhibitors were discovered, which did not clear all of the parasites from 3T3 host cells following 48 hours exposure, and were identified as putative T. cruzi cytochrome P450 (TcCYP51) inhibitors. TcCYP51 inhibitors are not favourable for the drug discovery pipeline for treatment of Chagas Disease infection due to clinical and pre-clinical failures...
March 20, 2018: Scientific Reports
Shehu S Awandu, Jaishree Raman, Takalani I Makhanthisa, Philip Kruger, John Frean, Teun Bousema, Jandeli Niemand, Lyn-Marie Birkholtz
BACKGROUND: Primaquine (PQ) is recommended as an addition to standard malaria treatments in pre-elimination settings due to its pronounced activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for onward transmission to mosquitoes. However, PQ may trigger haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. Additional human genetic factors, including polymorphisms in the human cytochrome P450 2D6 (CYP2D6) complex, may negatively influence the efficacy of PQ...
March 20, 2018: Malaria Journal
Eris Tollkuci
Midostaurin is the first approved FMS-related tyrosine kinase 3 (FLT3) inhibitor indicated for FLT3 mutated acute myeloid leukemia. Midostaurin is a major cytochrome P450 3A4 (CYP3A4) substrate. Coadministration with a strong CYP3A4 inhibitor or inducer can lead to a potential increase or decrease in midostaurin exposure. This report describes a 43-year-old patient with FLT3-internal tandem duplication (FLT3-ITD) positive acute myeloid leukemia who initially presented with leukocytosis and concern for acute leukemia...
January 1, 2018: Journal of Oncology Pharmacy Practice
Nazanin Abolhassani, Julien Castioni, Valérie Santschi, Gérard Waeber, Pedro Marques-Vidal
BACKGROUND: Polypharmacy (PP) and excessive polypharmacy (EPP) are increasingly common and associated with risk of drug-drug interactions (DDIs). We aimed to measure the trends and determinants of PP and DDIs among patients discharged from the Department of Internal Medicine of the Lausanne University Hospital. METHODS: The retrospective study included 17,742 adult patients discharged between 2009 and 2015. Polypharmacy and EPP were defined as the concomitant prescription of five or more and ten or more drugs, respectively...
March 19, 2018: Journal of Patient Safety
Rosa I Sanchez, Kerry L Fillgrove, Ka Lai Yee, Yuexia Liang, Bing Lu, Aditya Tatavarti, Rachael Liu, Matt S Anderson, Martin O Behm, Li Fan, Yun Li, Joan R Butterton, Marian Iwamoto, Sauzanne G Khalilieh
Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, ∼200 µCi) trial (N = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (N = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials...
March 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Akifumi Kogame, Ronald Lee, Liping Pan, Miyako Sudo, Masami Nonaka, Yuu Moriya, Tomoaki Higuchi, Yoshihiko Tagawa
1. The absorption, distribution, metabolism and excretion of fasiglifam were investigated in rats, dogs, and humans. 2. The absolute oral bioavailability of fasiglifam was high in all species (> 76.0%). 3. After oral administration of [14 C]fasiglifam, the administered radioactivity was quantitatively recovered and the major route of excretion of radioactivity was via feces in all species. 4. Fasiglifam was a major component in the plasma and feces in all species. Its oxidative metabolite (M-I) was observed as a minor metabolite in rat and human plasma (< 10% of plasma radioactivity)...
March 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Tony K L Kiang
Elbasvir and grazoprevir, in a fixed-dose combination of 50 and 100 mg, respectively, have received approval to be administered orally once daily, with or without ribavirin, for the treatment of chronic hepatitis C virus (HCV) infections. The absorption characteristics of elbasvir and grazoprevir have been adequately summarized, although differences were observed for grazoprevir (e.g., increased exposure at steady state in patients), but not elbasvir, between healthy and HCV-infected subjects. Inconsistencies with respect to absorption were also reported on the effects of food or acid reducers (famotidine or pantoprazole) in the literature...
March 20, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Frédérique Rodieux, Laszlo Vutskits, Klara M Posfay-Barbe, Walid Habre, Valérie Piguet, Jules A Desmeules, Caroline F Samer
Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children's inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults...
2018: Frontiers in Pharmacology
Rehab M Abdel Megeed, Dalia B Fayed, Amira Abood, Mai O Kadry
Although, fluconazole is widely used in clinical treatment as an antifungal drug, it recorded potential problems as resistance and intracellular accumulation. Female albino mice were injected with single ip dose of Candida albicans (1.5 × 106 CFU) . Three weeks post treatment with fluconazole and two novel synthesized compounds [(2-(4-(Pyridin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridin-2-yl) pyridine-3carbonitrile) and (2-(4-(Pyrimidin-2-yl) aminosulfonylphenylamino)-6-(naphthalen-2-yl)-4-(pyridine-2-yl)pyridine-3-carbonitrile) (13b & 14b, respectively)] in both low and high doses (50 mg/kg & 200 mg/kg), liver function and vaginal inflammation were assessed...
March 2018: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
Ewa Bromek, Marta Rysz, Anna Haduch, Jacek Wojcikowski, Władysława Anna Daniel
Our recent work suggested a negative effect for the serotonergic innervation of the paraventricular nuclei (PVN) of the hypothalamus on growth hormone secretion and growth hormone-dependent expression of cytochrome P450 2C11 (CYP2C11). The aim of our present research was to determine the effect of the activation of the 5-HT1 or 5-HT2 receptors in the PVN on the expression and activity of cytochrome P450 in male rat liver. The serotonergic agonists 5-CT (5-carboxyamidotryptamine, a 5-HT1 receptor-type agonist), 8-OH-DPAT (8-hydroxy-2-(di-n-propyloamino)-tetralin, a 5-HT1A receptor agonist), sumatriptan (a 5-HT1B/D receptor agonist) and DOI (2,5-dimethoxy-4-iodoamphetamine, a 5-HT2A/C receptor agonist) were individually injected into the PVN...
March 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Danica E DeGroot, Adam Swank, Russell S Thomas, Mark Strynar, Mi-Young Lee, Paul L Carmichael, Steven O Simmons
The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to false positive (chemical is detoxified in vivo) as well as false negative results (chemical is bioactivated in vivo) and thus potential mischaracterization of chemical hazard. To address this challenge, the ten most prevalent human liver cytochrome P450 (CYP) enzymes were introduced into a human cell line (HEK293T) with low endogenous metabolic capacity...
March 16, 2018: Journal of Pharmacological and Toxicological Methods
Manar Hamed Arafa, Hebatallah Husseini Atteia
Our objective was to figure out whether CYP2D6 gene polymorphisms may account for long term tramadol-induced oxidative stress and hepatotoxicity in 60 patients receiving chronic tramadol treatment in Neurology and Rheumatology Outpatients Clinic, Zagazig University Hospitals, Egypt. As expected, CYP2D6*1 allele (wild type) frequency was significantly greater than CYP2D6*DUP, CYP2D6*4 and CYP2D6*10 alleles in both chronically tramadol-treated and control groups. CYP2D6*DUP allele carriers followed by those carrying CYP2D6*1, displayed higher levels of urinary tramadol major active metabolite O-desmethyltramadol (M1) and serum lipid peroxidation along with lower levels of total antioxidants than those carrying other impaired function alleles (CYP2D6*4&*10) in tramadol-treated patients, suggesting oxidative stress...
March 16, 2018: Toxicology and Applied Pharmacology
Siriporn Chamniansawat, Chattraporn Sawatdiyaphanon
It is widely known that not only the gonadal estradiol (E2) but also hippocampal E2 plays an essential role in memory process. However, the role of hippocampal E2-enhanced memory mechanism during aging is largely unknown. The aim of the present study was to investigate the effect of age on E2 concentration, the expression level of its receptors, and key steroidogenic enzymes in hippocampus. We also investigated the effect of microglia activation on E2 synthesis in hippocampal neurons. The results showed that serum E2 was higher in 19-month-old (aged) rats, which exhibited spatial memory decline in the Morris water maze (MWM) test when compared to the younger rats...
January 1, 2018: International Journal of Toxicology
Anna A Perez-Umphrey, Christine M Bergeon Burns, Philip C Stouffer, Stefan Woltmann, Sabrina S Taylor
The seaside sparrow (Ammodramus maritimus) is an abundant and permanent resident of coastal salt marshes impacted by the 2010 BP Deepwater Horizon oil spill. Such terrestrial species are often overlooked in the aftermath of marine spills, despite the potential for long-term oil exposure. We sampled the livers of seaside sparrows residing in oiled and unoiled sites from 2011 to 2014 and quantified expression of cytochrome p450 1A (CYP1A), a gene involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs)...
March 1, 2018: Science of the Total Environment
Jan F de Boer, Vincent W Bloks, Esther Verkade, M Rebecca Heiner-Fokkema, Folkert Kuipers
PURPOSE OF REVIEW: There is a growing awareness that individual bile acid species exert different physiological functions, beyond their classical roles in bile formation and fat absorption, due to differential stimulatory effects on the bile-acid-activated receptors farnesoid X receptor (FXR) and takeda G receptor 5 (TGR5). This review integrates recent findings on the role of individual bile acids and their receptors in metabolic control, with special emphasis on cholesterol homeostasis...
March 16, 2018: Current Opinion in Lipidology
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