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Petr Jeřábek, Jan Florián, Václav Martínek
Cytochrome P450 1A2 (P450 1A2, CYP1A2) is a membrane-bound enzyme that oxidizes a broad range of hydrophobic substrates. The structure and dynamics of both the catalytic and trans-membrane (TM) domains of this enzyme in the membrane/water environment were investigated using a multiscale computational approach, including coarse-grained and all-atom molecular dynamics. Starting from the spontaneous self-assembly of the system containing the TM or soluble domain immersed in randomized dilauroyl phosphatidylcholine (DLPC)/water mixture into their respective membrane-bound forms, we reconstituted the membrane-bound structure of the full-length P450 1A2...
September 26, 2016: Physical Chemistry Chemical Physics: PCCP
Shiv Bahadur, Pulok K Mukherjee, S K Milan Ahmmed, Amit Kar, Ranjit K Harwansh, Subrata Pandit
OBJECTIVE: Tinospora cordifolia is used for treatment of several diseases in Indian system of medicine. In the present study, the inhibition potential of T. cordifolia extracts and its constituent tinosporaside to cause herb-drug interactions through rat and human liver cytochrome enzymes was evaluated. MATERIALS AND METHODS: Bioactive compound was quantified through reverse phase high-performance liquid chromatography, to standardize the plant extracts and interaction potential of standardized extract...
September 2016: Indian Journal of Pharmacology
Emily Urry, Alexander Jetter, Hans-Peter Landolt
BACKGROUND: Coffee consumption is a known inducer of cytochrome P450 1A2 (CYP1A2) enzyme activity. We recently observed that a group of type-2 diabetes patients consumed more caffeine (coffee) on a daily basis than non-type-2 diabetes controls. Here, we investigated whether type-2 diabetes cases may metabolize caffeine faster than non-type-2 diabetes controls. METHODS: To estimate CYP1A2 enzyme activity, an established marker of caffeine metabolism, we quantified the paraxanthine/caffeine concentration ratio in saliva in 57 type-2 diabetes and 146 non-type-2 diabetes participants in a case-control field study...
2016: Nutrition & Metabolism
Masashi Sekimoto, Haruna Sumi, Takuomi Hosaka, Takashi Umemura, Akiyoshi Nishikawa, Masakuni Degawa
The ability of nine cooked food-derived heterocyclic aromatic amines (HCAs), such as 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-amino-6-methylpyrido[12-a:3',2'-d]imidazole (Glu-P-1), 2-amino-pyrido[12-a:3',2'-d]imidazole hydrochloride (Glu-P-2), 2-amino-9H-pyrido[2,3-b]indole (AαC), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC), 2-amino-3-methylimidazo[4,5-f]quinolone (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PhIP), to activate human aryl hydrocarbon receptor (hAhR) was examined using a HepG2-A10 cell line, which has previously established from human hepatocarcinoma-derived HepG2 cells for use in hAhR-based luciferase reporter gene assays...
September 16, 2016: Food and Chemical Toxicology
Ume-Kulsoom Shah, Anna L Seager, Paul Fowler, Shareen H Doak, George E Johnson, Sharon J Scott, Andrew D Scott, Gareth J S Jenkins
Benzo[a]pyrene (B[a]P) is a known genotoxin and carcinogen, yet its genotoxic response at low level exposure has not been determined. This study was conducted to examine the interplay of dose and metabolic capacity on genotoxicity of B[a]P. Investigating and better understanding the biological significance of low level chemical exposures will help improve human health risk assessments. The genotoxic and mutagenic effects of B[a]P were investigated using human cell lines (AHH-1, MCL-5, TK6 and HepG2) with differential expression of the CYP450 enzymes CYP1A1, 1B1 and1A2 involved in B[a]P metabolism...
September 15, 2016: Mutation Research. Genetic Toxicology and Environmental Mutagenesis
Weiru Jiang, Xiangge Tian, Yan Wang, Zheng Sun, Peipei Dong, Chao Wang, Xiaokui Huo, Baojing Zhang, Shanshan Huang, Sa Deng, Xiaobo Wang, Xiaochi Ma
Melatonin (Mel) as an endogenous hormone, has been widely used in clinic for multiple therapeutic purposes. Further, the natural anthraquinones were widespread in various plants including herbs, foods, and some flavoring agents. The present work aims to evaluate the metabolic disorder of Mel caused by various common herbs and further identify their underlying mechanism. More importantly, the relationships between inhibitory activity and their structures were also investigated. Our results demonstrate that some herbs containing anthraquinone derivatives exhibited strong inhibition on Mel metabolism...
September 12, 2016: Toxicology Letters
Janina Burk, Amelie Plenge, Walter Brehm, Sandra Heller, Bastian Pfeiffer, Cornelia Kasper
Tendon and ligament pathologies are still a therapeutic challenge, due to the difficulty in restoring the complex extracellular matrix architecture and biomechanical strength. While progress is being made in cell-based therapies and tissue engineering approaches, comprehensive understanding of the fate of progenitor cells in tendon healing is still lacking. The aim of this study was to investigate the effect of decellularized tendon matrix and moderate cyclic stretching as natural stimuli which could potentially direct tenogenic fate...
2016: Stem Cells International
Tsutomu Shimada, Kensaku Kakimoto, Shigeo Takenaka, Nobuyuki Koga, Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki, Donghak Kim, Frederick Peter Guengerich, Masayuki Komori
2,5,2',5'-Tetrachlorobiphenyl (TCB) induced Type I binding spectra with cytochrome P450 (P450 or CYP) 2A6 and 2A13, having Ks values of 9.4 and 0.51 μM, respectively. However, CYP2A6 oxidized 2,5,2',5'-TCB to form 4-hydroxylated products at a much higher rate (~1.0 min-1) than CYP2A13 (~0.02 min-1), based on analysis by LC-MS/MS. Formation of 4-hydroxy-2,5,2',5'-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2',5'-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2',5'-TCB...
September 13, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Hua-Qiao Tang, Min Xu, Qian Rong, Ru-Wen Jin, Qi-Ji Liu, Ying-Lun Li
Zinc oxide (ZnO) is widely incorporated as a food additive in animal diets. In order to optimize the beneficial effects of ZnO and minimize any resultant environmental pollution, ZnO nanoparticles are often used for delivery of the zinc. However, the possible toxic effects of ZnO nanoparticles, including effects on cytochrome P450 (CYP450) enzymes, have not been evaluated. In this study, we investigated the effect of ZnO nanoparticles, in doses used in animal feeds, on CYP450 enzymes, liver and intestinal enzymes, liver and kidney histopathology, and hematologic indices in rats...
2016: International Journal of Nanomedicine
Hoa Thanh Nguyen, Maria Claret Lauan Tsuchiya, Jean Yoo, Midori Iida, Tetsuro Agusa, Masashi Hirano, Eun-Young Kim, Tatsuhiko Miyazaki, Masato Nose, Hisato Iwata
Dioxins cause various toxic effects through the aryl hydrocarbon receptor (AHR) in vertebrates, with dramatic species and strain differences in susceptibility. Although inbred mouse strains C3H/HeJ-lpr/lpr (C3H/lpr) and MRL/MpJ-lpr/lpr (MRL/lpr) are known as dioxin-sensitive and dioxin-resistant mice, respectively, the molecular mechanism underlying this difference remains unclear. The difference in the hepatic proteome of the two mouse strains treated with vehicle or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) was investigated by a proteomic approach of two-dimensional electrophoresis (2-DE) coupled with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF/TOF)...
September 7, 2016: Archives of Toxicology
Seong Eun Jin, Hyekyung Ha, Chang-Seob Seo, Hyeun-Kyoo Shin, Soo-Jin Jeong
OBJECTIVE: The purpose of this study was to investigate the potential influences of Socheongryong-tang (SCRT) on the messenger ribonucleic acid (mRNA) and protein expression of cytochrome P450 (CYP450) in vivo. MATERIALS AND METHODS: SCRT was orally administered to either male or female Sprague-Dawley rats once daily at doses of 0, 1000, 2000, or 5000 mg/kg/day for 13 weeks. The mRNA expression of CYP450s (CYP1A1, 1A2, 2B1/2, 2C11, 2E1, 3A1, 3A2, and 4A1) in liver tissues was measured by reverse transcription polymerase chain reaction...
July 2016: Pharmacognosy Magazine
Chao Wang, Xiaokui Huo, Xiangge Tian, Min Xu, Peipei Dong, Zhilin Luan, Xiaobo Wang, Baojing Zhang, Bo Zhang, Shanshan Huang, Sa Deng, Xiaochi Ma
BACKGROUND AND PURPOSE: Herbs which are widely used as food and medicine, are involved in many physiopathological processes. Melatonin is a human hormone, synthesized and secreted by the pineal gland, with a range of biological functions. Here, we have evaluated the potential influences of components extracted from common herbs on melatonin metabolism in humans. EXPERIMENTAL APPROACH: An in vivo pharmacokinetic study involving 12 healthy subjects, in vitro incubations with human liver microsomes (HLMs) and recombinant human cytochrome P (CYP) isoenzymes and an in silico quantitative structure-activity relationship (QSAR) model analysis using comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to explore these interactions...
September 2, 2016: British Journal of Pharmacology
Hiromi Soraoka, Kentaro Oniki, Kazuki Matsuda, Tatsumasa Ono, Kosuke Taharazako, Yoshihiro Uchiyashiki, Ryoko Kamihashi, Ayana Kita, Ayaka Takashima, Kazuko Nakagawa, Norio Yasui-Furukori, Daisuke Kadowaki, Keishi Miyata, Junji Saruwatari
The concomitant use of herb and prescription medications is increasing globally. Herb-drug interactions are therefore a clinically important problem. Yokukansan (YKS), a Japanese traditional herbal medicine, is one of the most frequently used herbal medicines. It is effective for treating the behavioral and psychological symptoms of dementia. We investigated the potential effects of YKS on drug-metabolizing enzyme activities in humans. An open-label repeat-dose study was conducted in 26 healthy Japanese male volunteers (age: 22...
2016: Biological & Pharmaceutical Bulletin
Y J Ma, D Q Jiang, J X Meng, M X Li, H H Zhao, Y Wang, L Q Wang
WHAT IS KNOWN AND OBJECTIVE: Numerous population pharmacokinetic studies of theophylline have been conducted in paediatric and adult patients. The purpose of this review was to summarize the published studies concerning population pharmacokinetics of theophylline in patients of different ages and discuss factors that might cause the large variability in the pharmacokinetics of theophylline. METHODS: A literature search was conducted in PubMed using the following keywords: 'theophylline', 'population pharmacokinetic(s)' and 'nonlinear mixed effect model'...
August 31, 2016: Journal of Clinical Pharmacy and Therapeutics
Ole Kristian Thu, Odd Georg Nilsen, Bent Hellum
CONTEXT: Rhodiola rosea L. (Crassulaceae) products are popular natural remedies with a worldwide distribution. Recent studies have revealed potent CYP inhibition by R. rosea extracts both in vitro and in vivo, but information on in vitro CYP inhibition by commercial products are lacking. Variations in commercial R. rosea product quality have also been published. OBJECTIVE: This study evaluates the variation of in vitro CYP inhibition potential and product quality of six commercially available R...
August 29, 2016: Pharmaceutical Biology
Takashi Satoh, Haruka Fujisawa, Ami Nakamura, Natsuko Takahashi, Kazuhiro Watanabe
PURPOSE: Green tea is a traditional beverage that has been enjoyed by the Japanese to this day. Recently, there has been an increase in the consumption of green tea beverage having high concentrations of catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG). Many people tend to ingest large amounts of catechins through the frequent consumption of green tea beverage, and this dietary habit may lead to unwanted interactions between the catechins in green tea and medicinal drug. METHODS: The inhibitory effects of eight green tea catechins on drug metabolizing enzymes, cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, were investigated in human liver microsomes...
April 2016: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
Johannes Matthaei, Mladen V Tzvetkov, Jakob Strube, Daniel Sehrt, Cordula Sachse-Seeboth, Jakob B Hjelmborg, Sören Möller, Ulrich Halekoh, Ute Hofmann, Matthias Schwab, Reinhold Kerb, Jürgen Brockmöller
Heritability of caffeine pharmacokinetics and CYP1A2 activity is controversial. Here we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic and dizygotic twins. In the entire group, common and unique environmental effects explained most variation in caffeine AUC. Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893)...
August 10, 2016: Clinical Pharmacology and Therapeutics
A Tagetti, U Ericson, M Montagnana, P Almgren, P M Nilsson, G Engstrom, B Hedblad, P Minuz, M Orho-Melander, O Melander, C Fava
OBJECTIVE: Between genetic variants pinpointed in genome wide association study there is the rs1378942 near the CYP1A1/CYP1A2 locus. Coffee consumption has been associated with blood pressure (BP) but with sometimes contrasting evidences. A part of BP-coffee relationship could be mediated by genetic mechanisms: that is single nucleotide polymorphisms (SNPs) nearby the CYP1A2 gene, which metabolize caffeine, could influence BP. Indeed, smoking habit induces the expression of the CYP1A2 enzyme whereas coffee consumption itself could increase CYP1A2 activity...
September 2016: Journal of Hypertension
Zhiyuan Qin, Lei Zhao, Haihong Hu, Huidi Jiang, Lushan Yu, Su Zeng
1. Cell models expressing human drug transporters and enzymes are useful tools to understand the process of drug disposition in vitro. However, no study on transfected cells stably co-expressing human organic anion transporter 1 (hOAT1) and/or human cytochrome P450 1A2 (hCYP1A2) is available. In this study, cell models stably expressing hOAT1 and/or hCYP1A2 were established, and were used to investigate the interactions of ingredients of herbal medicines (IHMs) with hOAT1 and/or hCYP1A2. 2. The MDCK cells were stable transfected with recombinant plasmids expressing hOAT1 and/or hCYP1A2...
August 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
M L Perepechaeva, N G Kolosova, N A Stefanova, A Zh Fursova, A Y Grishanova
Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2)...
August 2016: Experimental and Molecular Pathology
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