Database : MEDLINE
Search on : drug-induced and liver and injury [Words]
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[PMID]: 29523775
[Au] Autor:Schloss M; Becak D; Tosto ST; Velayati A
[Ad] Address:Medical Student, Alabama College of Osteopathic Medicine, Dothan, AL, USA.
[Ti] Title:A Case of Levofloxacin-Induced Hepatotoxicity.
[So] Source:Am J Case Rep;19:272-276, 2018 Mar 10.
[Is] ISSN:1941-5923
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND Levofloxacin covers a broad spectrum of pathogens and is readily prescribed by clinicians. Hepatotoxicity is a known but unusual complication of levofloxacin use. Here, we present a case of severe transaminitis caused by levofloxacin. CASE REPORT A young man in his thirties with a history of asthma, chronic alcoholism, methamphetamine intravenous drug abuse (IVDA), and non-compliant insulin-dependent diabetes mellitus (IDDM) presented to an emergency department with suicidal ideation. Vital signs were stable and the patient was noted to have cellulitis of the right forearm, for which cultures were drawn, and he received IV clindamycin. He was admitted to behavioral medicine for further care. Blood cultures were positive for gram-negative rods and he was transferred to the medicine ward. Cultures eventually grew Brevundimonas diminuta. Clindamycin was discontinued and he was started on levofloxacin. Transaminase levels measured soon after levofloxacin administration showed aminotransferase levels raised to approximately 50 times baseline within a few days. Levofloxacin was discontinued due to concern about drug-induced hepatotoxicity. After discontinuation, transaminase levels decreased immediately. Work-up for other causes of transaminitis revealed no other etiology. CONCLUSIONS Clinicians should remain mindful that levofloxacin can induce hepatotoxicity in rare cases. In patients presenting with acute liver injury who have recently taken levofloxacin, it would be wise to remain cognizant of the possibility of levofloxacin-induced hepatotoxicity.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Process

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[PMID]: 29523613
[Au] Autor:Perdigoto DN; Amaro P; Ferreira M; Tom L
[Ad] Address:Department of Gastroenterology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.
[Ti] Title:Flupirtine drug-induced liver injury in a patient developing acute liver failure.
[So] Source:BMJ Case Rep;2018, 2018 Mar 09.
[Is] ISSN:1757-790X
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:A patient is admitted with complaints of recent onset nausea, discomfort, jaundice and blood tests that reveal severe hepatitis. At the time, she had been taking medication with (St John's wort) for 6 months, and 6 weeks before this event, she took flupirtine maleate. A few days after being admitted, she developed encephalopathy progressing to acute liver failure (ALF) requiring unsuccessful liver transplantation. The patient was ultimately diagnosed with drug-induced liver injury (DILI). In this context, while could interfere with other medication or trigger DILI itself, flupirtine appears to have triggered the DILI, given its liver toxicity capacity. DILI is one of the major ALF causes and can jeopardise patient's life. Accordingly, all efforts to reduce medication potentially hazardous to the liver are recommended.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Process

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[PMID]: 29464936
[Au] Autor:Asthana A; White CM; Douglass M; Kisaalita WS
[Ad] Address:School of Chemical, Materials, and Biomedical Engineering, Cellular Bioengineering Laboratory, College of Engineering, Driftmier Engineering Center, University of Georgia, Athens, GA, 30602.
[Ti] Title:Evaluation of cellular adhesion and organization in different microporous polymeric scaffolds.
[So] Source:Biotechnol Prog;, 2018 Feb 21.
[Is] ISSN:1520-6033
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The lack of prediction accuracy during drug development and screening risks complications during human trials, such as drug-induced liver injury (DILI), and has led to a demand for robust, human cell-based, in vitro assays for drug discovery. Microporous polymer-based scaffolds offer an alternative to the gold standard flat tissue culture plastic (2D TCPS) and other 3D cell culture platforms as the porous material entraps cells, making it advantageous for automated liquid handlers and high-throughput screening (HTS). In this study, we optimized the surface treatment, pore size, and choice of scaffold material with respect to cellular adhesion, tissue organization, and expression of complex physiologically relevant (CPR) outcomes such as the presence of bile canaliculi-like structures. Poly-l-lysine and fibronectin (FN) coatings have been shown to encourage cell attachment to the underlying substrate. Treatment of the scaffold surface with NaOH followed with a coating of FN improved cell attachment and penetration into pores. Of the two pore sizes we investigated (A: 104 4 m; B: 175 6 m), the larger pore size better promoted cell penetration while limiting tissue growth from reaching the hypoxia threshold. Finally, polystyrene (PS) proved to be conducive to cell growth, penetration into the scaffold, and yielded CPR outcomes while being a cost-effective choice for HTS applications. These observations provide a foundation for optimizing microporous polymer-based scaffolds suitable for drug discovery. 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher
[do] DOI:10.1002/btpr.2627

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[PMID]: 29431329
[Au] Autor:Belyaeva NN; Sycheva LP
[Ti] Title:[Morphological comparative assessment of in vivo 2-week oral exposure of silver nanoparticles and silver sulfate on the mice liver].
[So] Source:Gig Sanit;95(9):899-902, 2016.
[Is] ISSN:0016-9900
[Cp] Country of publication:Russia (Federation)
[La] Language:rus
[Ab] Abstract:Currently the problem of the impact of nanoparticles and nanomaterials on human health remains to be poorly understood. As in our studies of the impact of silver nanoparticles on rats liver as well in works of other researchers there were investigated morphofunctional indices under peroral exposure. Although all researchers took different sizes, doses and concentrations of silver nanoparticles, various exposure time and different stabilizers, the same effects had been obtained, which, however, were occurred under both different doses and time of exposure. However, it was interesting to compare the impact of silver nanoparticles with reference substance - silver sulfate on the mice liver with the previously evaluated effect produced on the rats ' liver. By ourselves there was executed the morphological comparative evaluation of in vivo oral 2-weeks exposure of 4 concentrations (0.1; 5; 50 and 500 mg/l) of silver nanoparticles with size of 14 nm, stable arabian gum 1:7 by weight, and of 4 similar concentrations of silver sulfate on the liver of male mice СВАхС57В1/6 weighing 25-35g. 2 groups were considered as control: intact mice and mice received gum in water. Results of the exposure were assessed according to 10 morphological and functional indices. The impact of nanosilver was shown to initiate from its concentration of 50 mg/l and to express in the gain of the index of alteration of the cytoplasm of hepatocytes with the increasing in both severity of steatosis and the number of micronecroses, persisting at the same level at concentrations of 500 mg/l and with the elevation of the index of alteration of nuclei of hepatocytes, while the similar effect develops under the influence of silver sulfate at a concentration of 500 mg/l only. The remaining investigated morphofunctional indices did not differ significantly in all groups of mice. Unlike previously executed studies on rats, mice appeared to be sensitive to the effects of nano-silver more than to silver sulfate.
[Mh] MeSH terms primary: Chemical and Drug Induced Liver Injury
Fatty Liver
Liver
Nanostructures
Silver Compounds
[Mh] MeSH terms secundary: Administration, Oral
Animals
Chemical and Drug Induced Liver Injury/diagnosis
Chemical and Drug Induced Liver Injury/etiology
Disease Models, Animal
Fatty Liver/chemically induced
Fatty Liver/pathology
Hep G2 Cells
Humans
Liver/drug effects
Liver/pathology
Mice
Nanostructures/chemistry
Nanostructures/toxicity
Necrosis
Silver Compounds/chemistry
Silver Compounds/toxicity
Toxicity Tests/methods
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Silver Compounds)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:180213
[St] Status:MEDLINE

  5 / 26396 MEDLINE  
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[PMID]: 29288428
[Au] Autor:Scappaticci GB; Marini BL; Nachar VR; Uebel JR; Vulaj V; Crouch A; Bixby DL; Talpaz M; Perissinotti AJ
[Ad] Address:Department of Pharmacy Services and Clinical Sciences, Michigan Medicine and University of Michigan College of Pharmacy, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA.
[Ti] Title:Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.
[So] Source:Ann Hematol;97(4):573-584, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:The 5-year overall survival (OS) in patients ≥ 60years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60years old with AML treated with FLAG or CLO over the past 10years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.
[Mh] MeSH terms primary: Adenine Nucleotides/therapeutic use
Aging
Antimetabolites, Antineoplastic/therapeutic use
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Arabinonucleosides/therapeutic use
Induction Chemotherapy
Leukemia, Myeloid, Acute/drug therapy
Vidarabine/analogs & derivatives
[Mh] MeSH terms secundary: Adenine Nucleotides/adverse effects
Adenine Nucleotides/economics
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic/adverse effects
Antimetabolites, Antineoplastic/economics
Antineoplastic Combined Chemotherapy Protocols/adverse effects
Antineoplastic Combined Chemotherapy Protocols/economics
Arabinonucleosides/adverse effects
Arabinonucleosides/economics
Case-Control Studies
Chemical and Drug Induced Liver Injury/economics
Chemical and Drug Induced Liver Injury/epidemiology
Chemical and Drug Induced Liver Injury/mortality
Chemical and Drug Induced Liver Injury/therapy
Cohort Studies
Combined Modality Therapy/economics
Cost Savings
Costs and Cost Analysis
Cytarabine/adverse effects
Cytarabine/economics
Cytarabine/therapeutic use
Granulocyte Colony-Stimulating Factor/adverse effects
Granulocyte Colony-Stimulating Factor/economics
Granulocyte Colony-Stimulating Factor/therapeutic use
Hospital Costs
Humans
Incidence
Induction Chemotherapy/adverse effects
Induction Chemotherapy/economics
Length of Stay
Leukemia, Myeloid, Acute/economics
Leukemia, Myeloid, Acute/mortality
Michigan/epidemiology
Middle Aged
Neutropenia/chemically induced
Neutropenia/economics
Neutropenia/mortality
Neutropenia/therapy
Propensity Score
Retrospective Studies
Survival Analysis
Tertiary Care Centers
Vidarabine/adverse effects
Vidarabine/economics
Vidarabine/therapeutic use
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Name of substance:0 (Adenine Nucleotides); 0 (Antimetabolites, Antineoplastic); 0 (Arabinonucleosides); 04079A1RDZ (Cytarabine); 143011-72-7 (Granulocyte Colony-Stimulating Factor); 762RDY0Y2H (clofarabine); FA2DM6879K (Vidarabine)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:171231
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3217-1

  6 / 26396 MEDLINE  
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[PMID]: 29268129
[Au] Autor:Cen J; Guo H; Hong C; Lv J; Yang Y; Wang T; Fang D; Luo W; Wang C
[Ad] Address:Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
[Ti] Title:Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.
[So] Source:Eur J Med Chem;144:128-136, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] Country of publication:France
[La] Language:eng
[Ab] Abstract:A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced -amyloid (A) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, invivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.
[Mh] MeSH terms primary: Biphenyl Compounds/chemistry
Biphenyl Compounds/pharmacology
Cholinesterase Inhibitors/chemistry
Cholinesterase Inhibitors/pharmacology
Cognition/drug effects
Tacrine/analogs & derivatives
Tacrine/pharmacology
[Mh] MeSH terms secundary: Acetylcholinesterase/metabolism
Alzheimer Disease/drug therapy
Alzheimer Disease/pathology
Animals
Biphenyl Compounds/toxicity
Cell Line
Chemical and Drug Induced Liver Injury/etiology
Chemical and Drug Induced Liver Injury/pathology
Cholinesterase Inhibitors/toxicity
Cholinesterases/metabolism
Drug Design
Hep G2 Cells
Humans
Liver/drug effects
Liver/pathology
Male
Mice, Inbred ICR
PC12 Cells
Rats
Tacrine/toxicity
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Biphenyl Compounds); 0 (Cholinesterase Inhibitors); 0G32E321W1 (bifendate); 4VX7YNB537 (Tacrine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Cholinesterases)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:171222
[St] Status:MEDLINE

  7 / 26396 MEDLINE  
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[PMID]: 29441966
[Au] Autor:Zhao H; Meng W; Li Y; Liu W; Fu B; Yang Y; Zhang Q; Chen G
[Ti] Title:The protective effects of CHIR99021 against oxidative injury in LO2 cells.
[So] Source:Pharmazie;71(11):629-635, 2016 11 02.
[Is] ISSN:0031-7144
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Hepatic ischemia-reperfusion injury is one of the most important factors for the prognosis of liver transplantation and hepatic surgery. It was reported that glycogen synthase kinase-3 (GSK-3) regulated injury response during ischemia-reperfusion. In this study, we investigated the protective effects of the GSK-3 inhibitor CHIR99021 against hepatic ischemia-reperfusion injury. A H2O2-induced oxidative injury model using LO2 cells was established. LO2 cells were divided into four groups, including blank control group, CHIR99021 control group treated with CHIR99021 alone, H2O2-injury group treated with H2O2 and protection group treated with H2O2 plus CHIR99021. Cell viability, cell apoptosis or necrosis was determined. Meanwhile, mitochondrial membrane potential, lipid peroxidation, cellular ROS levels, SOD activity, and serum contents of ALS and AST were measured. Protein and mRNA expressions were also detected. The results showed that a cell oxidative injury model was established by treating LO2 cells with 200 mol/L H2O2 for 6 h. Cells exposed to H2O2 resulted in a significant decrease of cell viability and increase of cell apoptosis, which was accompanied by increasing ROS levels, disruption of mitochondrial membrane potential, excessive lipid peroxidation, reduction of SOD activity, and increased levels of ALT and AST. Treatment with CHIR99021 significantly protected LO2 cells against H2O2-induce oxidative injury by inhibiting the changes of above oxidative injury related indicators. Moreover, CHIR99021 treatment significantly reversed H2O2-induced decrease in p-GSK-3Ser9 , Bcl-2, Bcl-xl, survivin and -catenin expression, whereas it significantly attenuated H2O2-induced increase in caspase-3, cleaved caspase-3 and p-JNK protein expression. In conclusion, CHIR99021 protected LO2 cells against H2O2-induced oxidative injury through reducing GSK-3 activity and apoptosis, with underlying mechanisms involved in stabilizing mitochondrial membrane potential, attenuating cellular ROS generation, suppressing mitochondria-mediated apoptotic pathway, and activation of GSK-3/-catenin signaling pathway.
[Mh] MeSH terms primary: Cytoprotection/drug effects
Hepatocytes/drug effects
Oxidative Stress/drug effects
Pyridines/pharmacology
Pyrimidines/pharmacology
[Mh] MeSH terms secundary: Antioxidants/metabolism
Apoptosis/drug effects
Cell Line
Cell Survival/drug effects
Chemical and Drug Induced Liver Injury/enzymology
Chemical and Drug Induced Liver Injury/pathology
Chemical and Drug Induced Liver Injury/prevention & control
Glycogen Synthase Kinase 3/biosynthesis
Glycogen Synthase Kinase 3/genetics
Humans
Hydrogen Peroxide/pharmacology
Membrane Potential, Mitochondrial/drug effects
Necrosis
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antioxidants); 0 (Chir 99021); 0 (Pyridines); 0 (Pyrimidines); BBX060AN9V (Hydrogen Peroxide); EC 2.7.11.26 (Glycogen Synthase Kinase 3)
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[Js] Journal subset:IM
[Da] Date of entry for processing:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6714

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[PMID]: 29441915
[Au] Autor:Cao L-; Yan M; Ma YX; Zhang BK; Fang PF; Xiang DX; Li ZH; Gong H; Deng Y; Li HD
[Ti] Title:Isoliquiritigenin protects against triptolide-induced hepatotoxicity in mice through Nrf2 activation.
[So] Source:Pharmazie;71(7):394-397, 2016 Jul 07.
[Is] ISSN:0031-7144
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Isoliquiritigenin, a flavonoid found in licorice, has been considered as an antioxidive and hepato-protective agent. Recent studies have shown that a possible mechanism for triptolide-induced hepatotoxicity is related to oxidative damage induced by reactive oxygen species. This study was done to investigate the protection effect of isoliquiritigenin against triptolide-induced hepatotoxicity and the mechanism involved. An acute liver injury model was established by intraperitoneal injection of triptolide (1.0 mg kg-1) in mice. Different doses of isoliquiritigenin (12.5, 25 and 50 mg kg-1) were employed as protection. The activities of AST, ALT, ALP and LDH in serum and levels of GSH, GPx, SOD, CAT and MDA in liver tissue were detected. The histopathological changes of liver tissues were observed after HE staining. The protein expression of Nrf2 was detected by western blot. Pretreatment with isoliquiritigenin significantly prevented the triptolide-induced hepatotoxicity indicated by reduced activities of AST, ALT, ALP and LDH. Moreover, isoliquiritigenin pretreatment also prevented from triptolide-induced hepatotoxicity by inhibiting MDA and restoring the levels of GSH, GPx, SOD and CAT. In addition, isoliquiritigenin could attenuate histopathological changes induced by triptolide. Furthermore, the results indicated that isoliquiritigenin pretreatment caused an increase in the protein expression of Nrf2. These results indicated that isoliquiritigenin could protect against triptolide-induced hepatotoxicity via activation of the Nrf2 pathway.
[Mh] MeSH terms primary: Chalcones/pharmacology
Chemical and Drug Induced Liver Injury/prevention & control
Diterpenes/antagonists & inhibitors
Diterpenes/toxicity
NF-E2-Related Factor 2/metabolism
Phenanthrenes/antagonists & inhibitors
Phenanthrenes/toxicity
Protective Agents/pharmacology
[Mh] MeSH terms secundary: Animals
Chemical and Drug Induced Liver Injury/pathology
Epoxy Compounds/antagonists & inhibitors
Epoxy Compounds/toxicity
Liver/drug effects
Liver/metabolism
Liver Function Tests
Male
Malondialdehyde/antagonists & inhibitors
Mice
Mice, Inbred ICR
NF-E2-Related Factor 2/drug effects
Oxidative Stress/drug effects
Signal Transduction/drug effects
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Chalcones); 0 (Diterpenes); 0 (Epoxy Compounds); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, mouse); 0 (Phenanthrenes); 0 (Protective Agents); 19ALD1S53J (triptolide); 4Y8F71G49Q (Malondialdehyde); B9CTI9GB8F (isoliquiritigenin)
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[Js] Journal subset:IM
[Da] Date of entry for processing:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6535

  9 / 26396 MEDLINE  
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[PMID]: 29357190
[Au] Autor:Church RJ; Kullak-Ublick GA; Aubrecht J; Bonkovsky HL; Chalasani N; Fontana RJ; Goepfert JC; Hackman F; King NMP; Kirby S; Kirby P; Marcinak J; Ormarsdottir S; Schomaker SJ; Schuppe-Koistinen I; Wolenski F; Arber N; Merz M; Sauer JM; Andrade RJ; van Bmmel F; Poynard T; Watkins PB
[Ad] Address:Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC.
[Ti] Title:Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort.
[So] Source:Hepatology;, 2018 Jan 22.
[Is] ISSN:1527-3350
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of fourteen promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n=192 and =81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n=55 and =92) and DILI patients (n=98, =28, and =143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total keratin 18 (K18), caspase cleaved K18 (ccK18), glutathione S-transferase alpha (GSTα), alpha fetoprotein (AFP), arginase-1 (ARG1), osteopontin (OPN), sorbitol dehydrogenase (SDH), fatty acid binding protein (FABP1), cadherin-5 (CDH5), macrophage colony stimulating factor receptor (MCSFR), paraoxonase 1 (PON1, normalized to prothrombin protein), and leucocyte cell-derived chemotaxin-2 (LECT2). Most candidate biomarkers were significantly altered in DILI cases compared to healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase (ALT) than miR-122 and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among the healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplant within 6 months of DILI-onset. Prediction of prognosis among DILI patients using Model for End-stage Liver Disease (MELD) was improved by incorporation of K18 and MCSFR levels. CONCLUSION: GLDH appears to be more useful than miR-122 in identifying DILI patients. K18, OPN and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management. This article is protected by copyright. All rights reserved.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher
[do] DOI:10.1002/hep.29802

  10 / 26396 MEDLINE  
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[PMID]: 28463418
[Au] Autor:Liu C; Sekine S; Song B; Ito K
[Ad] Address:Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
[Ti] Title:Use of Primary Rat Hepatocytes for Prediction of Drug-Induced Mitochondrial Dysfunction.
[So] Source:Curr Protoc Toxicol;72:14.16.1-14.16.10, 2017 May 02.
[Is] ISSN:1934-9262
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Mitochondrial dysfunction plays a central role in drug-induced liver injury. To evaluate drug-induced mitochondrial impairment, several isolated mitochondria- or cell line-based assays have been reported. Among them, culturing HepG2 cells in galactose provides a remarkable method to assess mitochondrial toxicity by activating mitochondrial aerobic respiration. We applied this assay to primary rat hepatocytes by culturing cells in galactose and hyperoxia to enhance the evaluation of metabolism-related drug-induced mitochondrial toxicity. Conventional culture of primary hepatocytes under high-glucose and hypoxic conditions could force cells to switch energy generation to glycolysis. By contrast, cells cultured in galactose and hyperoxia could maintain energy generation from mitochondrial aerobic respiration, which is consistent with physiological conditions, and consequently improve the susceptibility of cells to mitochondrial toxicants. Measuring the toxicities of test compounds in primary rat hepatocytes cultured in modified conditions provides a useful model to identify mitochondrial dysfunction-mediated drug-induced hepatotoxicity. 2017 by John Wiley & Sons, Inc.
[Mh] MeSH terms primary: Hepatocytes/drug effects
Mitochondrial Diseases/chemically induced
Mitochondrial Diseases/pathology
[Mh] MeSH terms secundary: Animals
Cell Respiration
Chemical and Drug Induced Liver Injury
Culture Media
Energy Metabolism
Forecasting
Galactose/metabolism
Hepatocytes/enzymology
Hyperoxia/metabolism
L-Lactate Dehydrogenase/analysis
Oxygen Consumption
Primary Cell Culture
Rats
Rats, Sprague-Dawley
Toxicity Tests
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Culture Media); EC 1.1.1.27 (L-Lactate Dehydrogenase); X2RN3Q8DNE (Galactose)
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[Js] Journal subset:IM
[Da] Date of entry for processing:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cptx.24


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