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CYP2E1 AND Mitochondria

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https://www.readbyqxmd.com/read/27040342/-drug-induced-nonalcoholic-steatohepatitis
#1
Mitsuhiko Miyamura, Junko Yokota, Toshiji Saibara
Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease characterized by intense liver steatosis accompanied by hepatocyte destruction, inflammation and fibrous, despite little or no history of alcoholic consumption. There are also cases of drug-induced secondary steatohepatitis. Drug-induced steatohepatitis is a relatively rare type of drug-induced liver disease, but close attention to the possible onset of steatohepatitis is needed when drugs with the potential to induce fatty liver are prescribed for long term use...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/26895385/aconitum-carmichaelii-protects-against-acetaminophen-induced-hepatotoxicity-via-b-cell-lymphoma-2-protein-mediated-inhibition-of-mitochondrial-dysfunction
#2
Gunhyuk Park, Ki Mo Kim, Songie Choi, Dal-Seok Oh
We previously reported the clinical profile of processed Aconitum carmichaelii (AC, Aconibal(®)), which included inhibition of cytochrome P450 (CYP) 2E1 activity in healthy male adults. CYP2E1 is recognized as the enzyme that initiates the cascade of events leading to acetaminophen (APAP)-induced toxicity. However, no studies have characterized its role in APAP-induced hepatic injury. Here, we investigated the protective effects of AC on APAP-induced hepatotoxicity via mitochondrial dysfunction. AC (5-500 μg/mL) significantly inhibited APAP-induced reduction of glutathione...
March 2016: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/26806632/relationship-between-coumarin-induced-hepatocellular-toxicity-and-mitochondrial-function-in-rats
#3
Yasuhiro Tanaka, Wataru Fujii, Hisako Hori, Yoshinori Kitagawa, Kiyokazu Ozaki
The manifestation of coumarin-induced hepatocellular toxicity may differ and depends on the frequency of administration to rats. A single coumarin dose induces hepatocellular necrosis while repeated doses induce only hepatocyte degeneration. However, the mechanism underlying these effects remains unclear. Therefore, we investigated the mechanism of coumarin-induced hepatotoxicity in rats. Coumarin was administered to male rats as a single dose or for 4 consecutive days, and samples were obtained 4 or 24 h after a single dose or 24 h after the repeated doses...
April 2016: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/26463279/subcellular-localization-of-rat-cyp2e1-impacts-metabolic-efficiency-toward-common-substrates
#4
COMPARATIVE STUDY
Jessica H Hartman, H Cass Martin, Andres A Caro, Amy R Pearce, Grover P Miller
Cytochrome P450 2E1 (CYP2E1) detoxifies or bioactivates many low molecular-weight compounds. Most knowledge about CYP2E1 activity relies on studies of the enzyme localized to endoplasmic reticulum (erCYP2E1); however, CYP2E1 undergoes transport to mitochondria (mtCYP2E1) and becomes metabolically active. We report the first comparison of in vitro steady-state kinetic profiles for erCYP2E1 and mtCYP2E1 oxidation of probe substrate 4-nitrophenol and pollutants styrene and aniline using subcellular fractions from rat liver...
December 2, 2015: Toxicology
https://www.readbyqxmd.com/read/26278393/role-of-cyp2e1-in-mitochondrial-dysfunction-and-hepatic-tissue-injury-in-alcoholic-and-non-alcoholic-diseases
#5
Mohamed A Abdelmegeed, Seung-Kwon Ha, Youngshim Choi, Mohammed Akbar, Byoung-Joon Song
Alcoholic fatty liver diseases (AFLD) and non-alcoholic fatty liver diseases (NAFLD) are two pathological conditions that are spreading worldwide. Both conditions are remarkably similar with regards to the pathophysiological mechanism and progression despite different causes. Oxidative stress-induced mitochondrial dysfunction through post-translational protein modifications and/or mitochondrial DNA damage has been a major risk factor in both AFLD and NAFLD development and progression. Cytochrome P450-2E1 (CYP2E1), a known important inducer of oxidative radicals in the cells, has been reported to remarkably increase in both AFLD and NAFLD...
August 17, 2015: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26238404/hyperlipidemia-exacerbates-cerebral-injury-through-oxidative-stress-inflammation-and-neuronal-apoptosis-in-mcao-reperfusion-rats
#6
Xiao-Lu Cao, Jing Du, Ying Zhang, Jing-Ting Yan, Xia-Min Hu
Recent studies showed that hyperglycemia enhanced brain damage when subjected to transient cerebral ischemic stroke. However, the etiologic link between them has been less known. In the present study, based on an experimental rat's model of hyperlipidemia combined with cerebral ischemia-reperfusion injury (I/R), we herein showed that hyperlipidemia induced by high-fat diet (HFD) resulted in considerable increase in serum triglycerides, cholesterol and low-density lipoprotein cholesterol, and remarkable decrease in serum high-density lipoprotein cholesterol, which associated with an exacerbation on neurological deficit, cerebral infarct and terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells in the ischemic hemisphere of cerebral I/R rats treated with HFD diet...
October 2015: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/26202644/pre-endurance-training-prevents-acute-alcoholic-liver-injury-in-rats-through-the-regulation-of-damaged-mitochondria-accumulation-and-mitophagy-balance
#7
Guo-Dong Ma, Yan-Huan Liu, Qing-Lai Zhang, Bao-Guo Zhang, Ning Zhao, Qiu-Ling Wang, Xiao-di Wang
AIM: The aim of this study is to investigate the effect of pre-endurance training on the prevention of alcohol-induced acute hepatic injury and on hepatic mitophagy. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into four groups: (1) control group, (2) 12-week exercise training group, (3) 5-day alcohol intake group, and (4) 12-week exercise training plus 5-day alcohol intake group. The rats were examined to determine the following: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), hypoxia-inducible factor-1α (HIF-1α), cytochrome P450 2E1 (CYP2E1), alcohol dehydrogenase (ADH), microtubule-associated protein 1 light chain 3 (LC3II), Beclin1 mRNA and protein expressions, mitochondrial reactive oxygen species (ROS) production, mitochondrial thiobarbituric acid-reactive substances (TBARS) level, aconitase and ATP synthase activities, mitochondrial inner membrane potential, NADH/NAD(+) ratio, triglyceride (TG), the number of mtDNA and mitochondrial respiration functions in liver tissue, and serum ALT and AST...
July 2014: Hepatology International
https://www.readbyqxmd.com/read/26173704/insulin-receptor-a-and-sirtuin-1-synergistically-improve-learning-and-spatial-memory-following-chronic-salidroside-treatment-during-hypoxia
#8
Kalpana Barhwal, Saroj K Das, Ashish Kumar, Sunil K Hota, Ravi B Srivastava
Hypoxia has been reported to cause hippocampal neurodegeneration resulting in learning and memory deficits. In the present study, we investigated the potential of salidroside, a glucoside derivative of tyrosol, in ameliorating hypoxia-induced neurodegeneration and memory impairment. Morris water maze test showed improvement in learning and spatial memory of salidroside-treated hypoxic rats correlating with increased dendritic intersections and arborization. Salidroside administration increased phosphorylation of insulin receptor subunit A (IRA) at Y972, Y1162/63, and Y1146 sites and subsequent activation of AMP-activated protein kinase (AMPK) α subunit isoforms pAMPKα1 and pAMPKα2 resulting in mitochondrial biogenesis...
October 2015: Journal of Neurochemistry
https://www.readbyqxmd.com/read/26035647/hcv-core-protein-uses-multiple-mechanisms-to-induce-oxidative-stress-in-human-hepatoma-huh7-cells
#9
Alexander V Ivanov, Olga A Smirnova, Irina Y Petrushanko, Olga N Ivanova, Inna L Karpenko, Ekaterina Alekseeva, Irina Sominskaya, Alexander A Makarov, Birke Bartosch, Sergey N Kochetkov, Maria G Isaguliants
Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using the truncated forms of HCV core, we have delineated several mechanisms by which it induces the oxidative stress. The N-terminal 36 amino acids of HCV core induced TGF\(\upbeta\)1-dependent expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4, both of which independently contributed to the production of reactive oxygen species (ROS)...
June 2015: Viruses
https://www.readbyqxmd.com/read/25892964/the-effects-of-insulin-pre-administration-in-mice-exposed-to-ethanol-alleviating-hepatic-oxidative-injury-through-anti-oxidative-anti-apoptotic-activities-and-deteriorating-hepatic-steatosis-through-srbep-1c-activation
#10
Jiangzheng Liu, Xin Wang, Zhengwu Peng, Tao Zhang, Hao Wu, Weihua Yu, Deqing Kong, Ying Liu, Hua Bai, Rui Liu, Xiaodi Zhang, Chunxu Hai
Alcoholic liver disease (ALD) has become an important liver disease hazard to public and personal health. Oxidative stress is believed to be responsible for the pathological changes in ALD. Previous studies have showed that insulin, a classic regulator of glucose metabolism, has significant anti-oxidative function and plays an important role in maintaining the redox balance. For addressing the effects and mechanisms of insulin pre-administration on ethanol-induced liver oxidative injury, we investigated histopathology, inflammatory factors, apoptosis, mitochondrial dysfunction, oxidative stress, antioxidant defense system, ethanol metabolic enzymes and lipid disorder in liver of ethanol-exposed mice pretreatment with insulin or not...
2015: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/25744306/high-fat-diet-decreases-energy-expenditure-and-expression-of-genes-controlling-lipid-metabolism-mitochondrial-function-and-skeletal-system-development-in-the-adipose-tissue-along-with-increased-expression-of-extracellular-matrix-remodelling-and-inflammation
#11
Myung-Sook Choi, Young-Je Kim, Eun-Young Kwon, Jae Young Ryoo, Sang Ryong Kim, Un Ju Jung
The aim of the present study was to identify the genes differentially expressed in the visceral adipose tissue in a well-characterised mouse model of high-fat diet (HFD)-induced obesity. Male C57BL/6J mice (n 20) were fed either HFD (189 % of energy from fat) or low-fat diet (LFD, 42 % of energy from fat) for 16 weeks. HFD-fed mice exhibited obesity, insulin resistance, dyslipidaemia and adipose collagen accumulation, along with higher levels of plasma leptin, resistin and plasminogen activator inhibitor type 1, although there were no significant differences in plasma cytokine levels...
March 28, 2015: British Journal of Nutrition
https://www.readbyqxmd.com/read/25704631/increased-mitochondrial-ros-formation-by-acetaminophen-in-human-hepatic-cells-is-associated-with-gene-expression-changes-suggesting-disruption-of-the-mitochondrial-electron-transport-chain
#12
Jian Jiang, Jacob J Briedé, Danyel G J Jennen, Anke Van Summeren, Karen Saritas-Brauers, Gert Schaart, Jos C S Kleinjans, Theo M C M de Kok
Acetaminophen (APAP) overdosage results in hepatotoxicity, but the underlying molecular mechanisms are still not completely understood. In the current study, we focused on mitochondrial-specific oxidative liver injury induced by APAP exposure. Owning to genetic polymorphisms in the CYP2E1 gene or varying inducibility by xenobiotics, the CYP2E1 mRNA level and protein activity vary extensively among individuals. As CYP2E1 is a known ROS generating enzyme, we chose HepG2 to minimize CYP2E1-induced ROS formation, which will help us better understand the APAP induced mitochondrial-specific hepatotoxicity in a subpopulation with low CYP2E1 activity...
April 16, 2015: Toxicology Letters
https://www.readbyqxmd.com/read/25662501/preparation-of-hydrophilic-c60-oh-10-2-hydroxypropyl-%C3%AE-cyclodextrin-nanoparticles-for-the-treatment-of-a-liver-injury-induced-by-an%C3%A2-overdose-of-acetaminophen
#13
Yoshitaka Umezaki, Daisuke Iohara, Makoto Anraku, Yoichi Ishitsuka, Tetsumi Irie, Kaneto Uekama, Fumitoshi Hirayama
Stable hydrophilic C60(OH)10 nanoparticles were prepared from 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and applied to the treatment of an acetaminophen overdose induced liver Injury. C60(OH)10 nanoparticles were produced by cogrinding α-CD, β-CD, γ-CD and HP-β-CD and characterized in terms of solubility, mean particle diameter, ζ-potential and long term dispersibility in water. Hydrophilic C60(OH)10 nanoparticles with particle sizes less than 50 nm were effectively produced by cogrinding HP-β-CD with C60(OH)10 at a molar ratio of 1:3 (C60(OH)10:CD)...
March 2015: Biomaterials
https://www.readbyqxmd.com/read/25465468/mitochondrial-dysfunction-and-tissue-injury-by-alcohol-high-fat-nonalcoholic-substances-and-pathological-conditions-through-post-translational-protein-modifications
#14
REVIEW
Byoung-Joon Song, Mohammed Akbar, Mohamed A Abdelmegeed, Kyunghee Byun, Bonghee Lee, Seung Kew Yoon, James P Hardwick
Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions...
2014: Redox Biology
https://www.readbyqxmd.com/read/25386744/cytochrome-p450-expression-in-mouse-brain-specific-isoenzymes-involved-in-phase-i-metabolizing-system-of-porphyrinogenic-agents-in-both-microsomes-and-mitochondria
#15
Jimena Lavandera, Silvina Ruspini, Alcira Batlle, Ana María Buzaleh
Brain cytochrome P450 (CYP) metabolizes a variety of drugs to produce their pharmacological effects within the brain. We have previously observed that porphyrinogenic agents altered CYP levels in brain. The aim of this work was to further study the involvement of mice brain mitochondrial and microsomal Phase I drug metabolizing system when porphyrinogenic agents, such as Enflurane, Isoflurane, allylisopropylacetamide, veronal, ethanol, and Griseofulvin were administered. To this end, CYP2E1, CYP2B1, and CYP3A4 expression were measured...
February 2015: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/25362106/demethyleneberberine-a-natural-mitochondria-targeted-antioxidant-inhibits-mitochondrial-dysfunction-oxidative-stress-and-steatosis-in-alcoholic-liver-disease-mouse-model
#16
Pengcheng Zhang, Xiaoyan Qiang, Miao Zhang, Dongshen Ma, Zheng Zhao, Cuisong Zhou, Xie Liu, Ruiyan Li, Huan Chen, Yubin Zhang
Excessive alcohol consumption induces oxidative stress and lipid accumulation in the liver. Mitochondria have long been recognized as the key target for alcoholic liver disease (ALD). Recently, the artificial mitochondria-targeted antioxidant MitoQ has been used to treat ALD effectively in mice. Here, we introduce the natural mitochondria-targeted antioxidant demethyleneberberine (DMB), which has been found in Chinese herb Cortex Phellodendri chinensis. The protective effect of DMB on ALD was evaluated with HepG2 cells and acutely/chronically ethanol-fed mice, mimicking two common patterns of drinking in human...
January 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/25319358/schisandrol-b-protects-against-acetaminophen-induced-hepatotoxicity-by-inhibition-of-cyp-mediated-bioactivation-and-regulation-of-liver-regeneration
#17
Yiming Jiang, Xiaomei Fan, Ying Wang, Pan Chen, Hang Zeng, Huasen Tan, Frank J Gonzalez, Min Huang, Huichang Bi
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner...
January 2015: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/25105919/potent-effects-of-flavonoid-rich-extract-from-rosa-laevigata-michx-fruit-against-hydrogen-peroxide-induced-damage-in-pc12-cells-via-attenuation-of-oxidative-stress-inflammation-and-apoptosis
#18
Min Liu, Youwei Xu, Xu Han, Chen Liang, Lianhong Yin, Lina Xu, Yan Qi, Yanyan Zhao, Jinyong Peng, Changkai Sun
Oxidative stress-induced neuronal death has an important role in the pathogenesis of neurodegenerative disorders. The effects and mechanisms of action of the total flavonoids (TFs) from Rosa laevigata Michx fruit against hydrogen peroxide (H2O2)-induced oxidative injury in PC12 cells were investigated in this study. The results demonstrated that the TFs protected against cell apoptosis, DNA and mitochondrial damage caused by H2O2 based on single cell gel electrophoresis, in situ terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL), flow cytometry and transmission electron microscope (TEM) assays...
2014: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/24894520/phenotyping-of-cyp450-in-human-liver-microsomes-using-the-cocktail-approach
#19
Dany Spaggiari, Laurent Geiser, Youssef Daali, Serge Rudaz
The cocktail approach is an advantageous strategy used to monitor the activities of several cytochromes P450 (CYPs) in a single test to increase the throughput of in vitro phenotyping studies. In this study, a cocktail mixture was developed with eight CYP-specific probe substrates to simultaneously evaluate the activity of the most important CYPs, namely, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and the CYP3A subfamily. After cocktail incubation in the presence of human liver microsomes (HLMs), the eight selected substrates and their specific metabolites were analyzed by ultra-high-pressure liquid chromatography and electrospray ionization quadrupole time-of-flight mass spectrometry...
August 2014: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/24783247/mechanisms-of-isoniazid-induced-idiosyncratic-liver-injury-emerging-role-of-mitochondrial-stress
#20
REVIEW
Urs A Boelsterli, Kang Kwang Lee
Idiosyncratic drug-induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient-specific and drug-specific mechanisms) leading to DILI are poorly understood. Among the patient-specific determinants of susceptibility to INH-associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug-metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial...
April 2014: Journal of Gastroenterology and Hepatology
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