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Edgars Jecs, Eric J Miller, Robert J Wilson, Huy H Nguyen, Yesim A Tahirovic, Brook M Katzman, Valarie M Truax, Michelle B Kim, Katie M Kuo, Tao Wang, Chi S Sum, Mary E Cvijic, Gretchen M Schroeder, Lawrence J Wilson, Dennis C Liotta
A structure-activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener 15a was found to be a potent CXCR4 inhibitor (IC50 = 33 nM in CXCL12-mediated Ca2+ flux) with enhanced stability in liver microsomes and reduced inhibition of CYP450 (2D6). The improved CXCR4 antagonist 15a has potential therapeutic application as a single agent or combinatory anticancer therapy...
February 8, 2018: ACS Medicinal Chemistry Letters
Jianyu Liu, Yabo Ouyang, Dexi Chen, Bo Yao, Dongdong Lin, Zhiqiang Li, Yunjin Zang, Huan Liu, Xiaoyue Fu
The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants...
February 14, 2018: International Immunopharmacology
Jessica H Brown, Prativa Das, Michael D DiVito, David Ivancic, Lay Poh Tan, Jason A Wertheim
A major challenge of maintaining primary hepatocytes in vitro is progressive loss of hepatocyte-specific functions, such as protein synthesis and cytochrome P450 (CYP450) catalytic activity. We developed a three-dimensional (3D) nanofibrous scaffold made from poly(L-lactide-co-glycolide) (PLGA) polymer using a newlyoptimizedwet electrospinning techniquethat resulted in a highly porous structure that accommodated inclusion of primary human hepatocytes. Extracellular matrix (ECM) proteins (type I collagen or fibronectin) at varying concentrations were chemically linked to electrospun PLGA using amine coupling to develop an in vitro culture system containing the minimal essential ECM components of the liver micro-environment that preserve hepatocyte function in vitro...
February 14, 2018: Acta Biomaterialia
Jade Huguet, Fleur Gaudette, Véronique Michaud, Jacques Turgeon
The objective of our study was to develop and validate a cocktail approach to allow the simultaneous characterization of various CYP450-mediated oxydations by human heart microsomes for nine probe drug substrates namely. ethoxyresorufin. bupropion. repaglinide. tolbutamide. bufuralol. chlorzoxazone. ebastine. midazolam and dodecanoic acid. The first validation step was conducted using recombinant human CYP450 isoenzymes by comparing activity measured for each probe drug as a function of 1) buffer used. 2) selectivity towards specific isoenzymes...
February 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Rui Hou, Chao Huang, Kaifeng Rao, Yiping Xu, Zijian Wang
Tris(2-butoxyethyl) phosphate (TBOEP) and tris(n-butyl) phosphate (TNBP) are the most commonly used alkyl organophosphate esters (alkyl-OPEs), and they increasingly accumulate in organisms and create potential health hazards. This study examined the metabolism of TNBP and TBOEP in Carassius carassius liver and intestinal microsomes and the production of their corresponding mono-hydroxylated and dealkylated metabolites. After 140 min of incubation with fish liver microsomes, the rapid depletion of TNBP and TBOEP were both best fitted to Michaelis-Menten model (at administrated concentrations ranged from 0...
February 13, 2018: Environmental Science & Technology
Sophie Gravel, Jean-Louis Chiasson, Suzanne Dallaire, Jacques Turgeon, Veronique Michaud
INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response...
February 8, 2018: BMJ Open
Xiaobei Luo, Kapish Gupta, Abhishek Ananthanarayanan, Zenan Wang, Lei Xia, Aimin Li, Rashidah Binte Sakban, Side Liu, Hanry Yu
Shortage of functional hepatocytes hampers drug safety testing and therapeutic applications because mature hepatocytes cannot be expanded and maintain functions in vitro. Recent studies have reported that liver progenitor cells can originate from mature hepatocytes in vivo. Derivation of proliferating progenitor cells from mature hepatocytes, and re-differentiation into functional hepatocytes in vitro has not been successful. Here we report the derivation of novel mesenchymal-like stem cells (arHMSCs) from adult rat hepatocytes...
February 12, 2018: Scientific Reports
Amanda Soler, Ian Hunter, Gregory Joseph, Rebecca Hutcheson, Brenda Hutcheson, Jenny Yang, Frank Fan Zhang, Sachindra Raj Joshi, Chastity Bradford, Katherine H Gotlinger, Rachana Maniyar, John R Falck, Spencer Proctor, Michal Laniado Schwartzman, Sachin A Gupte, Petra Rocic
Arterial stiffness plays a causal role in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome P450 (CYP450)-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and loosely associated with obesity in humans. However, the role of 20-HETE in the regulation of large artery remodeling in metabolic syndrome has not been investigated. We hypothesized that elevated 20-HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure...
February 8, 2018: Journal of Molecular and Cellular Cardiology
Ying Zhang, Lan Miao, Li Lin, Chang-Ying Ren, Jian-Xun Liu, Yi-Min Cui
BACKGROUND: Sailuotong (SLT) is a standard Chinese preparation made from extracts of Panax ginseng (ginseng), Ginkgo biloba (ginkgo), and Crocus sativus (saffron). Preliminary clinical trials and animal experiments have demonstrated that SLT could improve cognition of vascular dementia (VD). PURPOSE: To avoid incident drug-drug interaction which is easily encountered in patients of VD, the potential influence of SLT on main drug-metabolic cytochromes P450 enzymes (CYP450) was investigated...
January 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Barbara Pavan, Alessandro Dalpiaz, Luca Marani, Sarah Beggiato, Luca Ferraro, Donatella Canistro, Moreno Paolini, Fabio Vivarelli, Maria C Valerii, Antonietta Comparone, Luigia De Fazio, Enzo Spisni
Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice...
2018: Frontiers in Pharmacology
Jan Machal, Ota Hlinomaz
BACKGROUND: Various antiplatelet drugs are used following acute coronary syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes P-glycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation...
February 5, 2018: Current Vascular Pharmacology
Roshan Limbu, Graeme S Cottrell, Alister J McNeish
BACKGROUND AND PURPOSE: Increasing evidence suggests that the omega-3 polyunsaturated acids (n-3 PUFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are beneficial to cardiovascular health, promoting relaxation of vascular smooth muscle cells and vasodilation. Numerous studies have attempted to study these responses, but to date there has not been a systematic characterisation of both DHA and EPA mediated vasodilation in conduit and resistance arteries. Therefore, we aimed to fully characterise the n-3 PUFA-induced vasodilation pathways in rat aorta and mesenteric artery...
2018: PloS One
Yi-Wen Zhang, Xiao-Wei Zheng, Yu-Jia Liu, Luo Fang, Zong-Fu Pan, Mei-Hua Bao, Ping Huang
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 μmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay...
January 26, 2018: Pharmacology
Sherry-Ann Brown, Naveen Pereira
Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel...
January 30, 2018: Journal of Personalized Medicine
Jagadeesh Sundaramoorthy, Gyu Tae Park, Kyosuke Mukaiyama, Chigen Tsukamoto, Jeong Ho Chang, Jeong-Dong Lee, Jeong Hoe Kim, Hak Soo Seo, Jong Tae Song
In soybean, triterpenoid saponin is one of the major secondary metabolites and is further classified into group A and DDMP saponins. Although they have known health benefits for humans and animals, acetylation of group A saponins causes bitterness and gives an astringent taste to soy products. Therefore, several studies are being conducted to eliminate acetylated group A saponins. Previous studies have isolated and characterized the Sg-5 (Glyma.15g243300) gene, which encodes the cytochrome P450 72A69 enzyme and is responsible for soyasapogenol A biosynthesis...
2018: PloS One
Yinghao Wang, Shuisheng Wu, Chen Liu, Xuehua Lu, Zhihuang Chen
Herba Gelsemii elegantis (GE) has been frequently used as a Chinese folk medicine but has high acute toxicity. In Traditional Chinese Medicine, it may be detoxified by Ramulus et Folium Mussaendae pubescentis (MP), but the detoxification mechanism has remained elusive. The present study aimed to evaluate the detoxification mechanisms by which MP modulates the effect of GE in rats, including the inhibition of hepatic cytochrome P (CYP)450 and glutathione S-transferase (GST) enzymes. Male Sprague Dawley rats were orally administered GE at three doses (0...
January 2018: Experimental and Therapeutic Medicine
Shuting Wang, Xiange Tang, Tingting Yang, Jiong Xu, Jiaxin Zhang, Xiaodong Liu, Li Liu
1. Contributions of cytochrome P450 (CYP450) isoforms to drug metabolism are often predicted using relative activity factor (RAF) method, assuming RAF values were independent of probe. We aimed to report probe-dependent characteristic of RAF values using CYP3A4 or CYP2C9 probes. 2. Metabolism of four CYP3A4 probes (testosterone, midazolam, verapamil, and atorvastatin) and three CYP2C9 probes (tolbutamide, diclofenac and S-warfarin) in human liver microsomes (HLM) and cDNA-expressed recombinant CYP450 (Rec-CYP450) systems were characterized and RAFCL value was estimated as ratio of probe intrinsic clearance in HLM to that in Rec-CYP450...
January 29, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
J Faria, J Barbosa, R Moreira, O Queirós, F Carvalho, R J Dinis-Oliveira
BACKGROUND AND OBJECTIVE: Moderate to severe pain represent a heavy burden in patients' quality of life, and ultimately in the society and in healthcare costs. The aim of this review was to summarize data on tramadol and tapentadol adverse effects, toxicity, potential advantages and limitations according to the context of clinical use. DATABASES AND DATA TREATMENT: We compared data on the pharmacological and toxicological profiles of tramadol and tapentadol, after an extensive literature search in the U...
January 25, 2018: European Journal of Pain: EJP
Hafiz Mamoon Rehman, Muhammad Amjad Nawaz, Zahid Hussain Shah, Seung Hwan Yang, Gyuhwa Chung
Triterpenoid saponins are one of the most highly accumulated groups of functional components in soybean (Glycine max) and the oxidative reactions during their biosynthesis are required for their aglycone diversity. Natural mutants of soyasaponins in wild soybean (Glycine soja) are valuable resources for establishing the soyasaponin biosynthesis pathway and breeding new soybean varieties. In this study, we investigated the genetic mechanism behind the absence of group A saponins in a Korean wild soybean mutant, CWS5095...
February 2018: Plant Science: An International Journal of Experimental Plant Biology
Ling Guo, Ying Cui, Kaijun Hao
CONTEXT: Asiatic acid has been reported to possess a wide range of pharmacological activities. OBJECTIVE: This study investigates the effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of orally administered asiatic acid (20 mg/kg) with or without glycyrrhizin pretreatment (100 mg/kg/day for seven days) were investigated using a LC-MS method. Additionally, the Caco-2 cell transwell model and rat liver microsome incubation systems were used to investigate the potential mechanism of glycyrrhizin's effects on the pharmacokinetics of asiatic acid...
December 2018: Pharmaceutical Biology
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