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cytochrome P450 reductase

Yusuf Haydar Ertekin, Burkay Yakar, Hülya Ertekin, Ayşegül Uludağ, Murat Tekin
BACKGROUND: Drugs represent one of the etiologic causes of acute rhabdomyolysis (AR) with drug-induced rhabdomyolysis most commonly associated with HMG-CoA reductase inhibitors. AR etiology can also result from the use of diclofenac, a non-steroidal anti-inflammatory drug, and omeprazole, a proton pump inhibitor. Cases of AR triggered by pantoprazole have never before been reported, although it has been observed that its inclusion in multiple drug therapies can result in muscle events...
December 2015: Drug Saf Case Rep
Koroush Khalighi, Gang Cheng, Seyedabbas Mirabbasi, Bahar Khalighi, Yin Wu, Wuqiang Fan
Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped...
October 14, 2016: Journal of Thrombosis and Thrombolysis
Ignat Printsev, Daniel Curiel, Kermit L Carraway
The canonical function of the endoplasmic reticulum-associated degradation (ERAD) system is to enforce quality control among membrane-associated proteins by targeting misfolded secreted, intra-organellar, and intramembrane proteins for degradation. However, increasing evidence suggests that ERAD additionally functions in maintaining appropriate levels of a subset of membrane-associated proteins. In this 'quantity control' capacity, ERAD responds to environmental cues to regulate the proteasomal degradation of specific ERAD substrates according to cellular need...
October 14, 2016: Journal of Membrane Biology
Lai Peng, Stephanie Piekos, Grace L Guo, Xiao-Bo Zhong
The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation. Farnesoid X receptor (FXR) is critical for bile acid and lipid homeostasis in liver. However, the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear. Hence, we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 and Fxr-null mice at 6 different ages from prenatal to adult were used...
September 2016: Acta Pharmaceutica Sinica. B
Fang Xie, Xinxin Ding, Qing-Yu Zhang
Oral administration is the most commonly used route for drug treatment. Intestinal cytochrome P450 (CYP)-mediated metabolism can eliminate a large proportion of some orally administered drugs before they reach systemic circulation, while leaving the passage of other drugs unimpeded. A better understanding of the ability of intestinal P450 enzymes to metabolize various clinical drugs in both humans and preclinical animal species, including the identification of the CYP enzymes expressed, their regulation, and the relative importance of intestinal metabolism compared to hepatic metabolism, is important for improving bioavailability of current drugs and new drugs in development...
September 2016: Acta Pharmaceutica Sinica. B
Fuguo Shi, Xiaobing Li, Hong Pan, Li Ding
Rifampicin (RIF) is used in regimens for infections caused by Mycobacteria accompanied by serious adverse reactions. Rifampicin-quinone (RIF-Q) is a major autoxidation product of RIF. It is not clear whether RIF-Q plays a role in RIF induced adverse reactions. Investigation of the systemic exposure of RIF-Q is helpful to better understand the role of RIF-Q in RIF induced adverse reactions. In this study, a simple and reproducible high performance liquid chromatography-mass spectrometry (LC-MS) method involving a procedure to prevent the RIF from oxidation for simultaneous quantification of RIF and RIF-Q in rat plasma has been developed and validated, and applied to elucidate the systemic exposure of RIF-Q in rats...
September 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
Claire Parage, Emilien Foureau, Franziska Kellner, Vincent Burlat, Samira Mahroug, Arnaud Lanoue, Thomas Dugé de Bernonville, Monica Arias Londono, Ines Teto Carqueijeiro, Audrey Oudin, Sebastien Besseau, Nicolas Papon, Gaelle Glévarec, Lucia Atehortua, Nathalie Giglioli-Guivarc'h, Benoit St-Pierre, Marc Clastre, Sarah O'Connor, Vincent Courdavault
Expansion of the biosynthesis of plant specialized metabolites notably results from the massive recruitment of cytochrome P450s that catalyze multiple types of conversion of biosynthetic intermediates. For catalysis, P450s require a two-electron transfer catalyzed by shared cytochrome P450 oxido-reductases (CPR), making these auxiliary proteins an essential component of specialized metabolism. CPR isoforms usually group into two distinct classes with different proposed roles, namely involvement in primary and basal specialized metabolisms for class I and inducible specialized metabolism for class II...
September 29, 2016: Plant Physiology
Xiaoyang Xu, Aolin Zhang, Matthew S Halquist, Xinxu Yuan, Scott C Henderson, William L Dewey, Pin-Lan Li, Ningjun Li, Fan Zhang
Statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, are the first-line medications prescribed for the prevention and treatment of coronary artery diseases. The efficacy of statins has been attributed not only to their systemic cholesterol-lowering actions but also to their pleiotropic effects that are unrelated to cholesterol reduction. These pleiotropic effects have been increasingly recognized as essential in statins therapy. This study was designed to investigate the pleiotropic actions of simvastatin, one of the most commonly prescribed statins, on macrophage cholesterol homeostasis with a focus on lysosomal free cholesterol egression...
September 15, 2016: Journal of Cellular and Molecular Medicine
Tobias M Hedison, Sam Hay, Nigel S Scrutton
This perspective reviews single molecule and ensemble fluorescence spectroscopy studies of the three tissue specific nitric oxide synthase (NOS) isoenzymes and the related diflavin oxidoreductase cytochrome P450 reductase. The focus is on the role of protein dynamics and the protein conformational landscape and we discuss how recent fluorescence-based studies have helped in illustrating how the nature of the NOS conformational landscape relates to enzyme turnover and catalysis.
September 9, 2016: Nitric Oxide: Biology and Chemistry
Geum-Hwa Lee, Kyoung-Jin Oh, Hyung-Ryong Kim, Hye-Sook Han, Hwa-Young Lee, Keun-Gyu Park, Ki-Hoan Nam, Seung-Hoi Koo, Han-Jung Chae
Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks...
2016: Scientific Reports
Marie Stiborová, Radek Indra, Michaela Moserová, Eva Frei, Heinz H Schmeiser, Klaus Kopka, David H Phillips, Volker M Arlt
No abstract text is available yet for this article.
September 19, 2016: Chemical Research in Toxicology
Ikrame Amara, Elodie Pramil, Catherine Senamaud-Beaufort, Audrey Devillers, Rodney Macedo, Géraldine Lescaille, Johanne Seguin, Eric Tartour, François M Lemoine, Philippe Beaune, Isabelle de Waziers
Gene-directed enzyme pro-drug therapy (GDEPT) consists of expressing, in tumor cells, a suicide gene which converts a pro-drug into cytotoxic metabolites, in situ. In a previous work, we demonstrated that the combination of the suicide gene CYP2B6TM-RED (a fusion of a triple mutant of CYP2B6 with NADPH cytochrome P450 reductase) and cyclophosphamide (CPA) constituted a powerful treatment for solid tumors. In this work, we investigated the use of mesenchymal stem cells (MSCs) as cellular vehicles for the delivery of our suicide gene...
October 10, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
So Young Park, Chung Hyeon Kim, Ji Yoon Lee, Jang Su Jeon, Min Ju Kim, Song Hee Chae, Hyoung Chin Kim, Soo Jin Oh, Sang Kyum Kim
In this study, the hepatic expression of cytochrome P450 (CYP) enzymes, including CYP1A1/2, 2B1, 2C11, 2E1, 3A1/2, and 4A, was investigated in 5-week-old (insulinresistant state) and 11-week-old (diabetic) Zucker diabetic fatty (ZDF) rats. Serum glucose and glycated hemoglobin levels were increased in 11-week-old ZDF rats, but not in 5-weekold ZDF rats. Hyperinsulinemia was observed in both age groups. The microsomal protein, total CYP, CYP reductase, CYP1A1/2, and CYP3A1 levels did not differ between 5- and 11-week-old ZDF rats and their respective control rats, while CYP4A was up-regulated in both groups...
October 2016: Food and Chemical Toxicology
James R Reed, Wayne L Backes
Cytochromes P450 represent a family of enzymes, which are responsible for the oxidative metabolism of a wide variety of xenobiotics. Although the mammalian P450s require interactions with their redox partners in order to function, more recently, P450 system proteins have been shown to exist as multi-protein complexes that include the formation of P450•P450 complexes. Evidence has shown that the metabolism of some substrates by a given P450 can be influenced by the specific interaction of the enzyme with other forms of P450...
August 2016: Drug Metabolism Reviews
Karen M McCammon, Satya P Panda, Chuanwu Xia, Jung-Ja P Kim, Daniela Moutinho, Michel Kranendonk, Richard J Auchus, Eileen M Lafer, Debashis Ghosh, Pavel Martasek, Rekha Kar, Bettie Sue Masters, Linda J Roman
Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of cytochrome P450 17A1, 19A1, and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing cytochromes P450, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo Differential scanning calorimetry and limited trypsinolysis studies revealed a relatively unstable A287P compared with WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability...
September 23, 2016: Journal of Biological Chemistry
Irina Lazarova, Rumyana Simeonova, Vessela Vitcheva, Magdalena Kondeva-Burdina, Reneta Gevrenova, Dimitrina Zheleva-Dimitrova, Gokhan Zengin, Nikolay D Danchev
The aim of this study was to investigate the effect of Asphodeline lutea (L.) Rchb. dry root extract (ALE) administered alone and against carbon tetrachloride (CCl4)-induced liver injury in vitro/in vivo. The dried roots of A. lutea were extracted with 70% ethanol and was characterized with HPLC-UV. Hepatoprotective potential was investigated by in vivo/in vitro assays in Wistar rats as well as antioxidant properties. At concentrations ranging from 10 to 200μg/mL of ALE significant cytotoxic effects on isolated hepatocytes were found...
June 23, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Eshvendar Reddy Kasala, Lakshmi Narendra Bodduluru, Chandana C Barua, Ranadeep Gogoi
The present study is designed to assess the antioxidant and antitumor potential of luteolin against benzo(a)pyrene [B(a)P]-induced lung carcinogenesis in Swiss albino mice. Here, we reported that oral administration of B(a)P (50mg/kg body weight) to mice resulted in raised lipid peroxides (LPO), lung specific tumor markers such as carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) with concomitant decrease in the levels of both enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione-s-transferase (GST), and non-enzymatic antioxidants such as reduced glutathione (GSH), vitamin E and vitamin C...
August 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Zeping Zhao, Matthew Barcus, Jonggun Kim, Krystal L Lum, Courtney Mills, Xin Gen Lei
BACKGROUND: Prolonged high intakes of dietary selenium have been shown to induce gestational diabetes in rats and hyperinsulinemia in pigs. OBJECTIVE: Two experiments were conducted to explore metabolic and molecular mechanisms for the diabetogenic potential of high dietary selenium intakes in pigs. METHODS: In Expt. 1, 16 Yorkshire-Landrace-Hampshire crossbred pigs (3 wk old, body weight = 7.5 ± 0.81 kg, 50% males and 50% females) were fed a corn-soybean meal basal diet supplemented with 0...
September 2016: Journal of Nutrition
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
Robert G Mothersole, Carla E Meints, Alex Louder, Kirsten R Wolthers
Cytochrome P450 reductase (CPR) contains a loop within the active site (comprising Asp(634), Ala(635), Arg(636) and Asn(637); human CPR numbering) that relocates upon NADPH binding. Repositioning of the loop triggers the reorientation of an FAD-shielding tryptophan (Trp(679)) to a partially stacked conformer, reducing the energy barrier for displacement of the residue by the NADPH nicotinamide ring: an essential step for hydride transfer. We used site-directed mutagenesis and kinetic analysis to investigate if the amino acid composition of the loop influences the catalytic properties of CPR...
September 15, 2016: Archives of Biochemistry and Biophysics
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