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Cytochrome P450

Michael S Samuel, Nicola Rath, Siti F Masre, Sarah T Boyle, David A Greenhalgh, Marina Kochetkova, Sheila Bryson, David Stevenson, Michael F Olson
The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream of the RhoA small GTP-binding protein. As a result, they have key roles in regulating cell morphology and proliferation, and have been implicated in numerous pathological conditions and diseases including hypertension and cancer. Here we describe the generation of a gene-targeted mouse line that enables CRE-inducible expression of a conditionally-active fusion between the ROCK2 kinase domain and the hormone-binding domain of a mutated estrogen receptor (ROCK2:ER)...
October 24, 2016: Genesis: the Journal of Genetics and Development
Salvador Alonso, Daniela Hernandez, Yu-Ting Chang, Christian D Gocke, Megan McCray, Ravi Varadhan, William H Matsui, Richard J Jones, Gabriel Ghiaur
Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid-low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche...
October 24, 2016: Journal of Clinical Investigation
Ryoichi Yano, Kyoko Takagi, Yoshitake Takada, Kyosuke Mukaiyama, Chigen Tsukamoto, Takashi Sayama, Akito Kaga, Toyoaki Anai, Satoru Sawai, Kiyoshi Ohyama, Kazuki Saito, Masao Ishimoto
Triterpenoid saponins are major components of secondary metabolites in soybean seeds and are divided into two groups: group A saponins and 2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP) saponins. The aglycone moiety of group A saponins consists of soyasapogenol A (SA), which is an oxidized β-amyrin product, and the aglycone moiety of the DDMP saponins consists of soyasapogenol B (SB). Group A saponins produce a bitter and astringent aftertaste in soy products, whereas DDMP saponins have known health benefits for humans...
October 24, 2016: Plant Journal: for Cell and Molecular Biology
Sharada Mahalingam, Liying Gao, Jacqueline Eisner, William Helferich, Jodi A Flaws
Isoliquiritigenin is a botanical estrogen used as a dietary supplement. Previous studies show that other botanical estrogens affect ovarian estradiol synthesis, but isoliquiritigenin's effects on the ovary are unknown. Thus, this study tested the hypothesis that isoliquiritigenin inhibits ovarian antral follicle growth and steroidogenesis. Antral follicles from CD-1 mice were cultured with vehicle control (dimethyl sulfoxide; DMSO) or isoliquiritigenin (0.6μM, 6 μM, 36 μM, and 100 μM) for 48-96hours. During culture, follicle diameters were measured daily to assess follicle growth...
October 20, 2016: Reproductive Toxicology
Marcos Guilherme da Cunha, Gilson César Nobre Franco, Marcelo Franchin, John A Beutler, Severino Matias de Alencar, Masaharu Ikegaki, Pedro Luiz Rosalen
In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array...
October 20, 2016: Toxicology Letters
Luqi Duan, John S Davis, Benjamin L Woolbright, Kuo Du, Mala Cahkraborty, James Weemhoff, Hartmut Jaeschke, Mohammed Bourdi
: Mouse models of acetaminophen (APAP) hepatotoxicity are considered relevant for the human pathophysiology. The C57BL/6 strain is most popular because it is the background strain of gene knock-out mice. However, conflicting results in the literature may have been caused by sub-strain mismatches, e.g. C57BL/6J and C57BL/6N. This study was initiated to determine the mechanism behind the sub-strain susceptibility to APAP toxicity. C57BL/6N and C57BL/6J mice were dosed with 200 mg/kg APAP and sacrificed at different time points...
October 20, 2016: Food and Chemical Toxicology
A D B Vliegenthart, R A Kimmitt, J H Seymour, N Z Homer, J I Clarke, M Eddleston, A Gray, D M Wood, P I Dargan, J G Cooper, D J Antoine, D J Webb, S C Lewis, D N Bateman, J W Dear
: Acetaminophen (paracetamol-APAP) is the commonest cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analysed from discovery (N=116) and validation (N=150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI...
October 22, 2016: Clinical Pharmacology and Therapeutics
Marilia N Siebert, Jacó J Mattos, Clei E Piazza, Daína de Lima, Carlos Henrique A M Gomes, Cláudio M R de Melo, Afonso C D Bainy
Cytochrome P450 family 1 (CYP1) is involved in polycyclic aromatic hydrocarbons (PAHs) biotransformation. PAHs can induce CYP1 protein expression and enzyme activity, the latter being usually quantified as 7-ethoxyresorufin O-deethylase activity (EROD). The aim of this study was to characterize EROD activity in the bivalve mollusk Crassostrea brasiliana. EROD activity was evaluated in cytosolic and microsomal fractions of gills, digestive gland and mantle of C. brasiliana. No EROD activity was detected in mantle, but it was present in microsomal fraction of gills and digestive gland with NADPH as coenzyme...
October 18, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Deepika Garg, Zaher Merhi
BACKGROUND: Women with PCOS have elevated levels of the harmful Advanced Glycation End Products (AGEs), which are highly reactive molecules formed after glycation of lipids and proteins. Additionally, AGEs accumulate in the ovaries of women with PCOS potentially contributing to the well-documented abnormal steroidogenesis and folliculogenesis. MAIN BODY: A systematic review of articles and abstracts available in PubMed was conducted and presented in a systemic manner...
October 21, 2016: Reproductive Biology and Endocrinology: RB&E
Jiaming Chen, Ying Peng, Jiang Zheng
Saracatinib, is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anti-cancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1-M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib...
October 21, 2016: Chemical Research in Toxicology
Kai Sheng, Jiahuan Lu
Quinones that exist in ambient particulate matter (PM) are hypothesized to be associated with adverse health effects through the generation of reactive oxygen species (ROS). However, the impacts of the quinones on the inflammatory processes have yet to be clearly understood. In this study, we examined the oxidative potentials and biological effects of typical airborne quinones in the human lung epithelial A549 cells. Significant change of redox status, loss of mitochondrial membrane potentials (△Ψ) and increase of superoxide dismutase (SOD) activity were induced by exposure to quinones...
October 21, 2016: Journal of Environmental Science and Health. Part A, Toxic/hazardous Substances & Environmental Engineering
Nathan R Unger, Marylee V Worley, Jamie J Kisgen, Elizabeth M Sherman, Lindsey M Childs-Kean
Current antiretrovirals (ARVs) have demonstrated the ability to prolong the life of an HIV infected individual via suppression of the virus and subsequent restoration of immune function. Despite significant advancement, there remains an opportunity for improvement. One ARV that attempts to fill global HIV therapeutic needs by balancing convenience, safety, and efficacy is elvitegravir (EVG). Areas covered: Using MEDLINE/PubMed, a literature search was conducted for published articles on the safety and efficacy of EVG in the treatment of HIV infection...
October 21, 2016: Expert Opinion on Pharmacotherapy
Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
October 21, 2016: Clinical Pharmacokinetics
Takayuki Koga, Pei-Li Yao, Maryam Goudarzi, Iain A Murray, Gayathri Balandaram, Frank J Gonzalez, Gary H Perdew, Albert J Fornace, Jeffrey M Peters
Alcoholic liver disease is a pathological condition caused by over-consumption of alcohol. Due to the high morbidity and mortality associated with this disease, there remains a need to elucidate the molecular mechanisms underlying its etiology and to develop new treatments. Since peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) modulates ethanol-induced hepatic effects, the present study examined alterations in gene expression that may contribute to this disease. Chronic ethanol treatment causes increased hepatic CYP2B10 expression in Pparβ/δ+/+ mice, but not in Pparβ/δ-/- mice...
October 20, 2016: Journal of Biological Chemistry
Juan Guillermo Cárcamo, Marcelo N Aguilar, Constanza F Carreño, Tamara Vera, Luis Arias-Darraz, Jaime E Figueroa, Alex P Romero, Marco Alvarez, Alejandro J Yañez
Rainbow trout (Oncorhynchus mykiss) subjected to three consecutive, alternating treatments with emamectin benzoate (EMB) and deltamethrin (DM) during outbreaks of Caligus rogercresseyi in a farm located in southern Chile (Hornopiren, Chiloé), were studied to determine the effects of these treatments on the protein and enzymatic activity levels of cytochrome P450 1A (CYP1A), flavin-containing monooxygenase (FMO) and glutathione S-transferase (GST) in different tissues. Consecutive and alternating EMB/DM treatments resulted in a 10-fold increase and 3-fold decrease of CYP1A protein levels in the intestine and gills, respectively...
October 17, 2016: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
Nicholas W Russo, Giovanna Petrucci, Bianca Rocca
Low-dose aspirin, alone or in combination, is recommended for the secondary prevention of acute non-cardioembolic ischemic stroke and transient ischemic attack, starting soon after the acute event. Clinically-relevant drug-drug interactions (DDIs) are a major concern of regulatory agencies and practicing physicians. Drug's pharmacodynamics and/or pharmacokinetics account for clinically-relevant DDIs that modify efficacy and/or safety of one or more of the co-administered drugs. Some non-steroidal anti-inflammatory drugs interact with aspirin pharmacodynamics by competing on the drug target, i...
October 17, 2016: Vascular Pharmacology
Laureen A Lammers, Roos Achterbergh, Marcel C M Pistorius, Yuma Bijleveld, Emmely M de Vries, Anita Boelen, Heinz-Josef Klümpen, Johannes A Romijn, RonA A Mathôt
BACKGROUND: The metabolic activity of P450 enzymes in vivo can be determined by using selective probe drugs. The simultaneous administration of multiple CYP-specific probe drugs is commonly referred to as the "cocktail approach." Disadvantages of a cocktail are large volumes of samples required for analysis and time-consuming analyses. The aim of this study was to develop and validate a simplified but sensitive method for the simultaneous quantification of five probe drugs (caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19), and S-warfarin (CYP2C9)) in a previously validated cocktail using an LC-MS/MS method...
October 19, 2016: Therapeutic Drug Monitoring
Lesley K Rao, Alicia M Flaker, Christina C Friedel, Evan D Kharasch
BACKGROUND: At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro...
October 20, 2016: Anesthesiology
Bera Rammohan, Karmakar Samit, Das Chinmoy, Saha Arup, Kundu Amit, Sarkar Ratul, Karmakar Sanmoy, Adhikari Dipan, Sen Tuhinadri
BACKGROUND: Traditionally GS is used to treat diabetes mellitus. Drug-herb interaction of GS via cytochrome P450 enzyme system by substrate cocktail method using HLM has not been reported. OBJECTIVE: To evaluate the in-vitro modulatory effects of GS extracts (aqueous, methanol, ethyl acetate, chloroform and n-hexane) and deacylgymnemic acid (DGA) on human CYP1A2, 2C8, 2C9, 2D6 and 3A4 activities in HLM. MATERIAL AND METHODS: Probe substrate-based LCMS/MS method was established for all CYPs...
July 2016: Pharmacognosy Magazine
Ewa Szwejser, B M Lidy Verburg-van Kemenade, Magdalena Maciuszek, Magdalena Chadzinska
Clinical and experimental evidence shows that estrogens affect immunity in mammals. Less is known about this interaction in the evolutionary older, non-mammalian, vertebrates. Fish form an excellent model to identify evolutionary conserved neuroendocrine-immune interactions: i) they are the earliest vertebrates with fully developed innate and adaptive immunity, ii) immune and endocrine parameters vary with season iii) physiology is constantly disrupted by increasing contamination of the aquatic environment...
October 16, 2016: Hormones and Behavior
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