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https://www.readbyqxmd.com/read/28527127/evaluation-of-heparg-cells-for-the-assessment-of-indirect-drug-induced-hepatotoxicity-using-inh-as-a-model-substance
#1
Anika Mann, Thomas Pelz, Knut Rennert, Alexander Mosig, Michael Decker, Amelie Lupp
HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin...
May 19, 2017: Human Cell
https://www.readbyqxmd.com/read/28526448/the-catechol-o-methyltransferase-inhibitors-tolcapone-and-entacapone-uncouple-and-inhibit-the-mitochondrial-respiratory-chain-in-heparg-cells
#2
David Grünig, Andrea Felser, Jamal Bouitbir, Stephan Krähenbühl
The catechol-O-methyltransferase inhibitor tolcapone causes hepatotoxicity and mitochondrial damage in animal models. We studied the interaction of tolcapone with mitochondrial respiration in comparison to entacapone in different experimental models. In HepaRG cells (human cell-line), tolcapone decreased the ATP content (estimated IC50 100±15μM) and was cytotoxic (estimated IC50 333±45μM), whereas entacapone caused no cytotoxicity and no ATP depletion up to 200μM. Cytochrome P450 induction did not increase the toxicity of the compounds...
May 16, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28525367/liposomal-co-delivered-oleanolic-acid-attenuates-doxorubicin-induced-multi-organ-toxicity-in-hepatocellular-carcinoma
#3
Muhammad Sarfraz, Attia Afzal, Shahid Masood Raza, Sajid Bashir, Asadullah Madni, Muhammad Waseem Khan, Xiang Ma, Guangya Xiang
Doxorubicin in combination with other cytotoxic drugs has clinical advantages. However, doxorubicin-induced cardiotoxicity negatively impacts clinical utility and outcomes. Cardiotoxicity can result from increased oxidative stress or from a local cytochrome P450 mediated increase in 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE). Oleanolic acid (OA) is a natural pentacyclic triterpenoid with free radical scavenging, cardioprotective, and P450-mediated cyclooxygenase-upregulating properties. We investigated co-delivery of liposomal OA and doxorubicin in a HepG2 model of hepatocellular carcinoma (HCC)...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28525288/inference-of-the-genetic-polymorphisms-of-cyp2d6-in-six-subtribes-of-the-malaysian-orang-asli-from-whole-genome-sequencing-data
#4
Choo Yee Yu, Geik Yong Ang, Vinothini Subramaniam, Richard Johari James, Aminuddin Ahmad, Thuhairah Abdul Rahman, Fadzilah Mohd Nor, Syahrul Azlin Shaari, Lay Kek Teh, Mohd Zaki Salleh
AIMS: CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study aims to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli. METHODS: Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing...
May 19, 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28525276/chemoenzymatic-total-synthesis-and-structural-diversification-of-tylactone-based-macrolide-antibiotics-through-late-stage-polyketide-assembly-tailoring-and-c-h-functionalization
#5
Andrew N Lowell, Matthew D DeMars, Samuel T Slocum, Fengan Yu, Krithika Anand, Joseph A Chemler, Nisha Korakavi, Jennifer K Priessnitz, Sung Ryeol Park, Aaron A Koch, Pamela J Schultz, David H Sherman
Polyketide synthases (PKSs) represent a powerful catalytic platform capable of effecting multiple carbon-carbon bond forming reactions and oxidation state adjustments. We explored the functionality of two terminal PKS modules that produce the 16-membered tylosin macrocycle, using them as biocatalysts in the chemoenzymatic synthesis of tylactone and its subsequent elaboration to complete the first total synthesis of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics via late-stage diversification...
May 19, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28525267/the-supernatant-from-hepatocyte-cultures-with-drugs-that-cause-idiosyncratic-liver-injury-activates-macrophage-inflammasomes
#6
Ryuji Kato, Jack Uetrecht
There is increasing evidence that most idiosyncratic drug-induced liver injury (IDILI) is immune mediated, and in most cases reactive metabolites appear to be responsible for induction of this immune response. Reactive metabolites can cause cell damage with the release of damage-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Presumably the reason that the liver is a common target of idiosyncratic drug reactions is because it is the major site of drug metabolism and reactive metabolite formation...
May 19, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28524079/assembly-of-hepatocyte-spheroids-using-magnetic-3d-cell-culture-for-cyp450-inhibition-induction
#7
Pujan K Desai, Hubert Tseng, Glauco R Souza
There is a significant need for in vitro methods to study drug-induced liver injury that are rapid, reproducible, and scalable for existing high-throughput systems. However, traditional monolayer and suspension cultures of hepatocytes are difficult to handle and risk the loss of phenotype. Generally, three-dimensional (3D) cell culture platforms help recapitulate native liver tissue phenotype, but suffer from technical limitations for high-throughput screening, including scalability, speed, and handling. Here, we developed a novel assay for cytochrome P450 (CYP450) induction/inhibition using magnetic 3D cell culture that overcomes the limitations of other platforms by aggregating magnetized cells with magnetic forces...
May 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28523515/distribution-of-exogenous-and-endogenous-cyp3a-markers-and-related-factors-in-healthy-males-and-females
#8
Jieon Lee, Andrew HyoungJin Kim, SoJeong Yi, SeungHwan Lee, Seo Hyun Yoon, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho
Cytochrome P450 (CYP) 3A is an important drug-metabolizing enzyme in humans. Assessing CYP3A activity is necessary for predicting therapeutic outcomes or the potential adverse events of various therapeutics. This study sought to evaluate the distribution of endogenous and exogenous markers reflecting hepatic CYP3A activity and related factors affecting its activity in healthy male and female. Each subject was given a single 1 mg dose of midazolam intravenously. Pharmacokinetics, pharmacometabolomics, and pharmacogenomics analyses were performed to evaluate CYP3A activity...
May 18, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28522909/in-vitro-and-in-vivo-antioxidative-and-hepatoprotective-activity-of-aqueous-extract-of-cortex-dictamni
#9
Lin Li, Yun-Feng Zhou, Yan-Lin Li, Li-Li Wang, Hiderori Arai, Yang Xu
AIM: To investigate the antioxidant and hepatoprotective effects of Cortex Dictamni aqueous extract (CDAE) in carbon tetrachloride (CCl4)-induced liver damage in rats. METHODS: The in vitro antioxidant effect of CDAE was investigated using α,α-diphenyl-β-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), β-carotene bleaching, reducing power, and thiobarbituric acid reactive substance assays. A linoleic acid system, including ferric thiocyanate (FTC) and thiobarbituric acid (TBA) assays, was used to evaluate the inhibition of lipid peroxidation...
April 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28522339/proteomics-analysis-of-fusarium-proliferatum-under-various-initial-ph-during-fumonisin-production
#10
Taotao Li, Liang Gong, Yong Wang, Feng Chen, Vijai Kumar Gupta, Qijie Jian, Xuewu Duan, Yueming Jiang
Fusarium proliferatum as a fungal pathogen can produce fumonisin which causes a great threat to animal and human health. Proteomic approach was a useful tool for investigation into mycotoxin biosynthesis in fungal pathogens. In this study, we analyzed the fumonisin content and mycelium proteins of Fusarium proliferatum cultivated under the initial pH5 and 10. Fumonisin production after 10days was significantly induced in culture condition at pH10 than pH5. Ninety nine significantly differently accumulated protein spots under the two pH conditions were detected using two dimensional polyacrylamide gel electrophoresis and 89 of these proteins were successfully identified by MALDI-TOF/TOF and LC-ESI-MS/MS analysis...
May 15, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28522317/the-association-between-cytochrome-p450-3a-progesterone-receptor-polymorphisms-plasma-17-ohpc-concentrations-and-spontaneous-preterm-birth
#11
Martha L Bustos, Steve N Caritis, Kathleen A Jablonski, Uma M Reddy, Yoram Sorokin, John M Thorp, Michael W Varner, Ronald J Wapner, Jay D Iams, Marshall W Carpenter, Alan M Peaceman, Brian M Mercer, Anthony Sciscione, Dwight J Rouse, Susan M Ramin
BACKGROUND: Infants born before 37 weeks' gestation are of public health concern since complications associated with preterm birth are the leading cause of mortality in children under 5 years of age and a major cause of morbidity and lifelong disability. The administration of 17-hydroxyprogesterone caproate (17-OHPC) reduces preterm birth by 33% in women with history spontaneous preterm birth (SPTB). We demonstrated previously that plasma concentrations of 17-OHPC vary widely among pregnant women and that women with 17-OHPC plasma concentrations in the lowest quartile had SPTB rates of 40% vs rates of 25% in those women with higher concentrations...
May 15, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/28521423/molecular-dysexpression-in-gastric-cancer-revealed-by-integrated-analysis-of-transcriptome-data
#12
Xiaomei Li, Weiwei Dong, Xueling Qu, Huixia Zhao, Shuo Wang, Yixin Hao, Qiuwen Li, Jianhua Zhu, Min Ye, Wenhua Xiao
Gastric cancer (GC) is often diagnosed in the advanced stages and is associated with a poor prognosis. Obtaining an in depth understanding of the molecular mechanisms of GC has lagged behind compared with other cancers. This study aimed to identify candidate biomarkers for GC. An integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between GC and normal tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed to identify the functions of the DEGs...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28521079/association-between-cyp4f2-genotype-and-circulating-plasma-vitamin-k-concentration-in-children-on-chronic-warfarin-therapy-possible-long-term-implications-for-bone-development-and-vascular-health
#13
Emmanouela Kampouraki, Peter J Avery, Tina Biss, Farhad Kamali
Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix-Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long-term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy...
May 18, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28520936/impacts-of-amino-acid-substitutions-in-fungal-cytochrome-p450-monooxygenase-cyp57b3-on-the-effective-production-of-3-hydroxygenistein
#14
Mayumi Hatakeyama, Takuya Kitaoka, Hirofumi Ichinose
Aspergillus oryzae cytochrome P450 monooxygenase (CYP57B3) is capable of catalyzing hydroxylation of genistein to produce 3΄-hydroxygenistein. Because hydroxylated derivatives of genistein, including 3΄-hydroxygenistein, exhibit various pharmacological activities, CYP57B3 would potentially be useful as a biocatalyst in the pharmaceutical field. We therefore performed random mutagenesis of CYP57B3 to improve its catalytic activities for genistein. Random mutations were introduced by error-prone PCR into CYP57B3, resulting in construction of a library of mutants...
May 18, 2017: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/28520411/alignment-based-prediction-of-sites-of-metabolism
#15
Christina de Bruyn Kops, Nils-Ole Friedrich, Johannes Kirchmair
Prediction of metabolically labile atom positions in a molecule (sites of metabolism) is a key component of the simulation of xenobiotic metabolism as a whole, providing crucial information for the development of safe and effective drugs. In 2008, an exploratory study was published in which sites of metabolism were derived based on molecular shape- and chemical feature-based alignment to a molecule whose site of metabolism (SoM) had been determined by experiments. We present a detailed analysis of the breadth of applicability of alignment-based SoM prediction, including transfer of the approach from a structure- to ligand-based method and extension of the applicability of the models from cytochrome P450 2C9 to all cytochrome P450 isozymes involved in drug metabolism...
May 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28515072/%C3%AF-3-and-%C3%AF-6-long-chain-pufas-and-their-enzymatic-metabolites-in-neovascular-eye-diseases
#16
REVIEW
Yan Gong, Zhongjie Fu, Raffael Liegl, Jing Chen, Ann Hellström, Lois Eh Smith
Neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, threaten the visual health of children and adults. Current treatment options, including anti-vascular endothelial growth factor therapy and laser retinal photocoagulation, have limitations and are associated with adverse effects; therefore, the identification of additional therapies is highly desirable. Both clinical and experimental studies show that dietary ω-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) reduce retinal and choroidal angiogenesis...
May 17, 2017: American Journal of Clinical Nutrition
https://www.readbyqxmd.com/read/28514663/fatty-acid-oxidation-in-zebrafish-adipose-tissue-is-promoted-by-1%C3%AE-25-oh-2d3
#17
Xuyan Peng, Guohui Shang, Wenqing Wang, Xiaowen Chen, Qiyong Lou, Gang Zhai, Dongliang Li, Zhenyu Du, Yali Ye, Xia Jin, Jiangyan He, Yi Zhang, Zhan Yin
1α,25(OH)2D3 (vitamin D3) is crucial for mineral homeostasis in mammals, but the precise effects of 1α,25(OH)2D3 in adipose tissue remain to be clarified in vivo. The initial 25-hydroxylation is catalyzed by liver microsomal cytochrome P450 2R1 (CYP2R1), which is conserved in vertebrates. To probe the physiological function(s) of 1α,25(OH)2D3 in teleosts, we generated two independent cyp2r1-deficient zebrafish lines. These mutants exhibit retarded growth and increased obesity, especially in the visceral adipose tissue (VAT)...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28514642/congenital-adrenal-hyperplasia-due-to-11-hydroxylase-deficiency-compound-heterozygous-mutations-of-a-prevalent-and-two-novel-cyp11b1-mutations
#18
Chongjuan Gu, Tao Tan, Junbao Yang, Yilu Lu, Yongxin Ma
11β-hydroxylase deficiency (11β-OHD) occurs in about 5-8% of congenital adrenal hyperplasia (CAH). In this study, we identified three CYP11B1 (encoding Cytochrome P450 11B1) heterozygous mutations: c.1358G>C (p.R453Q), c.1229T>G (p.L410R) and c.1231G>T (p.G411C) in a Chinese CAH patient due to classic 11β-OHD. His parents were healthy and respectively carried the prevalent mutation c.1358G>C (p.R453Q), and the two novel mutations c.1229T>G (p.L410R) and c.1231G>T (p.G411C). In vitro expression studies, immunofluorescence demonstrated that wild type and mutant (L410R and G411C) proteins of CYP11B1 were correctly expressed on the mitochondria, and enzyme activity assay revealed the mutant reduced the 11-hydroxylase activity to 10% (P<0...
May 14, 2017: Gene
https://www.readbyqxmd.com/read/28514338/-a-comparative-chemoreactome-analysis-of-mexidol
#19
I Yu Torshin, O A Gromova, I S Sardaryan, L E Fedotova
AIM: To compare mexidol with control molecules (choline alfoscerate, piracetam, glycine, semax) using chemoreactome analysis. MATERIAL AND METHODS: The chemical structure of mexidol was compared to molecule metabolites extracted from the Human Metabolome Database (HMDB) and a drug database. More than 40 000 of metabolites from HMDB were used as a model of human metabolome. RESULTS AND CONCLUSION: The chemoreactome analysis showed that mexidol may be (1) an agonist of acetylcholine and GABA-A receptors; (2) an anti-inflammatory agent, the effects of which are carried out by inhibiting the synthesis of pro-inflammatory prostaglandins; (3) a neurotrophic agent with neuroprotective properties; (4) a coagulation inhibitor; (5) a diabetes medication and (6) a hypolipidemic agent...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/28506817/in-vitro-cyp-mediated-drug-metabolism-in-the-zebrafish-embryo-using-human-reference-compounds
#20
Moayad Saad, An Matheeussen, Sebastiaan Bijttebier, Evy Verbueken, Casper Pype, Christophe Casteleyn, Chris Van Ginneken, Sandra Apers, Louis Maes, Paul Cos, Steven Van Cruchten
The increasing use of zebrafish embryos as an alternative model for toxicological and pharmacological studies necessitates a better understanding of xenobiotic biotransformation in this species. As cytochrome P450 enzymes (CYPs) play an essential role in this process, in vitro drug metabolism of four human CYP-specific substrates, i.e. dextromethorphan (DXM), diclofenac (DIC), testosterone (TST) and midazolam (MDZ) was investigated in adult male and female zebrafish, and in zebrafish embryos and larvae up to 120hours post-fertilization...
May 12, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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