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Laura Hedges, Susan Brown, A Kenneth MacLeod, Audrey Vardy, Edward Doyle, Gina Song, Marjory Moreau, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. 2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CLint ) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5...
May 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Meng-Ge Zhao, Xue-Ping Sheng, Ya-Ping Huang, Yi-Ting Wang, Cui-Hua Jiang, Jian Zhang, Zhi-Qi Yin
The effects of triterpenic acids-enriched fraction from Cyclocarya paliurus (CPT) on nonalcoholic fatty liver disease (NAFLD) were investigated using in vivo and in vitro models. In high fat diet-induced Wister rats, CPT significantly increased superoxide dismutase (SOD) activity and glutathione/oxidized glutathione (GSH/GSSG) ratio, reduced malondialdehyde (MDA) and protein carbonyl (PCO) levels. Moreover, CPT restored mitochondrial membrane potential dysfunction, decreased cytochrome P450 enzyme 2E1 (CYP2E1) activity, improved nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-mediated antioxidant enzyme heme oxygenase1 (HO-1) expression...
May 15, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Abhinav Parashar, Daniel Andrew Gideon, Kelath Murali Manoj
Recently, electron transfers and catalyses in a bevy of redox reactions mediated by hemeproteins were explained by murburn concept. The term "murburn" is abstracted from " mur ed burn ing " or " m ild u n r estricted burn ing " and connotes a novel " m olecule- u nbound ion- r adical " interaction paradigm. Quite unlike the genetic regulations and protein-level affinity-based controls that govern order and specificity/selectivity in conventional treatments, murburn concept is based on stochastic/thermodynamic regulatory principles...
April 2018: Dose-response: a Publication of International Hormesis Society
Xinping Ye, Xiangkun Wang, Liming Shang, Guangzhi Zhu, Hao Su, Chuangye Han, Wei Qin, Guanghui Li, Tao Peng
Objective: Acetaldehyde dehydrogenase 2 ( ALDH2 ) and cytochrome P450 2E1 ( CYP2E1 ) have been associated with hepatocellular carcinoma (HCC) susceptibility and prognosis. The polymorphisms ALDH2 rs671 and CYP2E1 rs2031920 are reportedly correlated with the prevalence of HCC in other countries. The aim of this study was to investigate associations between ALDH2 and CYP2E1 , and HCC susceptibility in a population of Guangxi, southern China, an area with a high incidence of HCC. Patients and methods: The study cohort included 300 HCC cases, 292 healthy controls for HCC susceptibility analysis, and another 20 HCC cases and 10 healthy controls for ascertainment...
2018: Cancer Management and Research
Takujiro Homma, Takaya Shirato, Ryusuke Akihara, Sho Kobayashi, Jaeyong Lee, Ken-Ichi Yamada, Satoshi Miyata, Motoko Takahashi, Junichi Fujii
Aldehyde reductase (Akr1a) has been reported to be involved in detoxification of reactive aldehydes as well as in the synthesis of bioactive compounds such as ascorbic acid (AsA). Because Akr1a is expressed at high levels in the liver and is involved in xenobiotic metabolism, our objective was to investigate the hepato-protective role of Akr1a in a thioacetamide (TAA)-induced hepatotoxicity model using Akr1a-deficient (Akr1a-/- ) mice. Wild-type (WT) and Akr1a-/- mice were injected intraperitoneally with TAA and the extent of liver injury in the acute phase was assessed...
May 12, 2018: Toxicology Letters
Ragu Ramanathan, Anima Ghosal, Lakshmi Ramanathan, Kate Comstock, Helen Shen, Dil Ramanathan
AIM: Evaluation of HPLC-high-resolution mass spectrometry (HPLC-HRMS) full scan with polarity switching for increasing throughput of human in vitro cocktail drug-drug interaction assay. MATERIALS & METHODS: Microsomal incubates were analyzed using a high resolution and high mass accuracy Q-Exactive mass spectrometer to collect integrated qualitative and quantitative (Qual/Quant) data. RESULTS: Within assay, positive-to-negative polarity switching HPLC-HRMS method allowed quantification of eight and two probe compounds in the positive and negative ionization modes, respectively, while monitoring for LOR and its metabolites...
May 11, 2018: Bioanalysis
Lucia Pellè, Henrik Carlsson, Monica Cipollini, Alessandra Bonotti, Rudy Foddis, Alfonso Cristaudo, Cristina Romei, Rossella Elisei, Federica Gemignani, Margareta Törnqvist, Stefano Landi
In a recent study, we demonstrated that the variant allele of rs2480258 within intron VIII of CYP2E1 is associated with reduced levels of mRNA, protein, and enzyme activity. CYP2E1 is the most important enzyme in the metabolism of acrylamide (AA) by operating its oxidation into glycidamide (GA). AA occurs in food, is neurotoxic and classified as a probable human carcinogen. The goal of the present study was to further assess the role of rs2480258 by measuring the rate of AA > GA biotransformation in vivo...
May 10, 2018: Archives of Toxicology
Hai Zhang, Haiyan Li, Huanxin Yu
Background: To explore the genetic effect of rs2031920 and rs3813867 polymorphisms within the cytochrome P450 2E1 ( CYP2E1 ) gene on the risk of squamous cell carcinoma (SCC), a meta-analysis was performed. Methods: The eligible case-control studies were obtained by database searching and screening, and the specific statistical analysis was performed with STATA 12.0 software. Results: After the process of database searching and screening, a total of 32 case-control studies with 7435 cases and 10,466 controls were ultimately included in our meta-analysis...
2018: Cancer Cell International
Siyang Tian, Yannick Djoumbou, Russ Greiner, David S Wishart
In silico metabolism prediction requires first predicting whether a specific molecule will interact with one or more specific metabolizing enzymes, then predicting the result of each enzymatic reaction. Here, we provide a computational tool, CypReact, for performing this first task of reactant prediction. Specically, CypReact takes as input an arbitrary molecule (specied as a SMILES string or a standard SDF file), and any one of the nine of the most important human cytochrome P450 (CYP450) enzymes -- CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 -- and accurately predicts whether the query molecule will react with that given CYP450 enzyme...
May 8, 2018: Journal of Chemical Information and Modeling
Yankai Wen, Chenchen Wang, Jinyang Gu, Chang Yu, Kaixia Wang, Xuehua Sun, Yun Sun, Hailong Wu, Ying Tong, Qiang Xia, Xiaoni Kong
Induction of osteopontin (OPN), a well-known pro-inflammatory molecule, has been observed in acetaminophen (APAP)-induced hepatotoxicity. However, the precise cell source for OPN induction and its role during APAP-induced hepatotoxicity has not been fully explored. By employing a hepatotoxic mouse model induced by APAP overdose, we demonstrate that both serum and hepatic OPN levels were significantly elevated in response to APAP treatment. Our in vivo and in vitro studies clearly indicated that the induced expression of hepatic OPN was mainly located in necrosis areas and produced by dying or dead hepatocytes...
May 7, 2018: Cellular & Molecular Immunology
Fei Shen, Zhaohong Wang, Wei Liu, Yuji Liang
The effects of ethyl pyruvate (EP) on alcoholic liver disease and its related mechanism were investigated. Thirty male C57/BL6 mice were randomly divided to three groups: Control (n=10), alcoholic liver disease (ALD, n=10) and ethyl pyruvate group (EP, n=10). EP group was treated with gavage using EP (100 mg/kg) for 15 consecutive days. Control and ALD group were treated with the same volume of normal saline. After the last gavage, EP and ALD group were treated with the intraperitoneal injection of 50% alcoholic solution (10 ml/kg)...
May 2018: Experimental and Therapeutic Medicine
Charatda Punvittayagul, Arpamas Chariyakornkul, Teera Chewonarin, Kanokwan Jarukamjorn, Rawiwan Wongpoomchai
Diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH) are classical carcinogens used in experimental rodent carcinogenesis. However, the interaction effects of these carcinogens on biochemical and molecular changes during carcinogenesis have not been investigated. Therefore, the effect of DEN and DMH co-administration on preneoplastic lesion formation and its molecular mechanism in rats were determined. Triple intraperitoneal administrations of DEN were made before, during or after double subcutaneous injections of DMH...
May 3, 2018: Drug and Chemical Toxicology
Tatsushi Toyooka, Yukie Yanagiba, Yuko Ibuki, Rui-Sheng Wang
Trichloroethylene (TCE), a chlorinated hydrocarbon, was recently reclassified as a human carcinogen by the International Agency for Research on Cancer. Genotoxic events are known to be crucial steps in the initiation of cancer. The genotoxic properties of TCE have been examined in many studies using a standard battery of genotoxicity tests both in vitro and in vivo. However, consistent results have not been obtained, and studies investigating the mechanism behind the genotoxicity of this compound are lacking...
May 3, 2018: Journal of Applied Toxicology: JAT
Jing Sun, Xiaozhu Tang, Qianqian Xu, Tao Ge, Daiyin Peng, Weidong Chen
BACKGROUND AND OBJECTIVES: Gambogenic acid (GNA), which possesses diverse antitumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. Cytochrome P450 (CYP) enzymes play an important role in the metabolism of most xenobiotics; constitutive androstane receptor (CAR), a nuclear receptor that might be activated by xenobiotics and associated with the expression of some CYPs. In this study, we determined the effect of GNA on multiple rat liver CYP isoforms (CYP1A2, 2B1, and 2E1) and CAR as well as the potential of GNA to interact with co-administered drugs...
May 2, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Pavan Kumar Bellamakondi, Ashok Godavarthi, Mohammed Ibrahim
Introduction: Paracetamol is a potent hepatotoxin and may cause severe acute hepatocellular injury. The present study was intended to assess the hepatoprotective potential of Caralluma umbellata Haw. (Asclepiadaceae) ( C. umbellata ) against paracetamol-induced hepatotoxicity in vitro and in vivo experimental models. Methods: Preliminary analysis for antioxidant and hepatoprotective property was evaluated for methanolic (MCU), aqueous (ACU) and hydro methanolic (HCU) extracts of C. umbellata using in vitro cell-free antioxidant such as DPPH, ABTS, nitric oxide, lipid peroxidation models and cell-based hepatoprotective study using BRL3A cells...
2018: BioImpacts: BI
Yong Zhang, Can Wang, Bin Yu, Jian-Dong Jiang, Wei-Jia Kong
This study aims to investigate the protective effects of gastrodin (GSTD), a natural compound isolated from the root of Gastrodia elata BL., on ethanol-induced liver injury and apoptosis in HepG2 cells and animal models. For in vitro studies, GSTD was used to pre-treat the cells for 4 h followed by 600 mM of ethanol co-administration for 24 h. Alcoholic liver disease (ALD) of Sprague-Dawley (SD) rats was induced by chronic ethanol-feeding plus a single dose (5 g/kg) of acute ethanol administration, GSTD at different doses were co-administered for 8 weeks...
2018: Biological & Pharmaceutical Bulletin
Mohammad A Rahman, Yuqing Gong, Santosh Kumar
Diallyl sulfide (DAS) has been shown to prevent xenobiotic (e.g. ethanol, acetaminophen) induced toxicity and disease (e.g. HIV-1) pathogenesis. DAS imparts its beneficial effect by inhibiting CYP2E1-mediated metabolism of xenobiotics, especially at high concentration. However, DAS also causes toxicity at relatively high dosages and with long exposure times. Therefore, the goal of the current study was to investigate the structural analogs of DAS for their improved toxicity profiles and their effectiveness in reducing xenobiotic-induced toxicity and HIV-1 replication...
April 22, 2018: Toxicology Letters
Sufan Wang, Ting Wan, Mingtong Ye, Yun Qiu, Lei Pei, Rui Jiang, Nengzhi Pang, Yuanling Huang, Baoxia Liang, Wenhua Ling, Xiaojun Lin, Zhenfeng Zhang, Lili Yang
BACKGROUND: Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+ ) precursor which is present in foods such as milk and beer. It was reported that NR can prevent obesity, increase longevity, and promote liver regeneration. However, whether NR can prevent ethanol-induced liver injuries is not known. This study aimed to explore the effect of NR on ethanol induced liver injuries and the underlying mechanisms. METHODS: We fed C57BL/6 J mice with Lieber-DeCarli ethanol liquid diet with or without 400 mg/kg·bw NR for 16 days...
April 5, 2018: Redox Biology
Firas Alhasson, Ratanesh Kumar Seth, Sutapa Sarkar, Diana A Kimono, Muayad S Albadrani, Diptadip Dattaroy, Varun Chandrashekaran, Geoffrey I Scott, Samir Raychoudhury, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Saurabh Chatterjee
High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21...
April 7, 2018: Redox Biology
Xiaofang Cui, Benting Ma, Yan Wang, Yan Chen, Chunling Shen, Ying Kuang, Jian Fei, Lungen Lu, Zhugang Wang
Mitochondrion-localized retinol dehydrogenase 13 (Rdh13) is a short-chain dehydrogenase/reductase involved in vitamin A metabolism in both humans and mice. We previously generated Rdh13 knockout mice and showed that Rdh13 deficiency causes severe acute retinal light damage. In this study, considering that Rdh13 is highly expressed in mouse liver, we further evaluated the potential effect of Rdh13 on liver injury induced by carbon tetrachloride (CCl4 ). Although Rdh13 deficiency showed no significant effect on liver histology and physiological functions under regular culture, the Rdh13-/- mice displayed an attenuated response to CCl4 -induced liver injury...
April 14, 2018: Frontiers of Medicine
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