Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatment.

Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, United States.
Toxicology (Impact Factor: 3.75). 04/2010; 272(1-3):32-8. DOI: 10.1016/j.tox.2010.03.015
Source: PubMed

ABSTRACT Among currently prescribed nonsteroidal anti-inflammatory drugs, sulindac (SLD) is associated with the greatest incidence of idiosyncratic hepatotoxicity in humans. Previously, an animal model of SLD-induced idiosyncratic hepatotoxicity was developed by cotreating rats with a nonhepatotoxic dose of LPS. Tumor necrosis factor-alpha (TNF) was found to be critically important to the pathogenesis. In this study, the mechanism of liver injury induced by SLD/LPS cotreatment was further explored. Protein carbonyls, products of oxidative stress, were elevated in liver mitochondria of SLD/LPS-cotreated rats. The results of analyzing gene expression in livers of rats before the onset of liver injury indicated that genes associated with oxidative stress were selectively regulated by SLD/LPS cotreatment. Antioxidant treatment with either ebselen or dimethyl sulfoxide attenuated SLD/LPS-induced liver injury. The role of oxidative stress was further investigated in vitro. SLD sulfide, the toxic metabolite of SLD, enhanced TNF-induced cytotoxicity and caspase 3/7 activity in HepG2 cells. SLD sulfide also increased dichlorofluorescein fluorescence, suggesting generation of reactive oxygen species (ROS). Hydrogen peroxide and TNF cotreatment of HepG2 cells caused greater cytotoxicity than either treatment alone. Either antioxidant tempol or a pancaspase inhibitor Z-VAD-FMK decreased cell death as well as caspase 3/7 activity induced by SLD sulfide/TNF coexposure. These results indicate that SLD/LPS treatment causes oxidative stress in livers of rats and suggest that ROS are important in SLD/LPS-induced liver injury in vivo. Furthermore, ROS contribute to the cytotoxic interaction of SLD and TNF by activating caspase 3/7.


Available from: Lyle D Burgoon, Dec 29, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical pharmacotherapy. However, prediction of DILI is difficult because the underlying mechanisms are not fully understood. To establish a novel cell-based screening system to suggest drugs with hepatotoxic potential in preclinical drug development, comprehensive gene expression analyses during in vivo DILI are necessary. Using in vivo mouse DILI models and 4 sets of hepatotoxic positive and non-hepatotoxic drugs, we found that the hepatic mRNA levels of S100A8; S100A9; “NATCH, LRR, and pyrin domain-containing protein 3” (NALP3); interleukin (IL)-1β; and the receptor for advanced glycation endproducts (RAGE) were commonly increased in hepatotoxic drug-administered mice compared to non-hepatotoxic drug-administered mice. To clarify whether these 5 in vivo biomarkers can be applied to a cell-based screening system, we adapted human liver microsomes (HLM) in the presence of NADPH to assess the metabolic activation reaction, and we also adapted human monocytic leukemia cells HL-60, K562, KG-1 and THP-1 to assess the effects on mRNA expression of immune- and inflammatory-related factors. We investigated 30 clinical drugs with different safety profiles with regard to DILI and found that the total sum score of gene expression levels of S100A8, S100A9, RAGE, NALP3 and IL-1β mRNA in HL-60 or K562 cells incubated with HLM, could identify drugs at high risk for hepatotoxicity. We proposed the use of the total sum score of gene expression level for assessing metabolic activation by drug-metabolizing enzymes and immune- and inflammatory-related factors for the risk assessment of DILI in preclinical drug development.
    Toxicology Letters 07/2014; DOI:10.1016/j.toxlet.2014.04.005 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study is focused on the pertinence of the seismic reprocessing done in the North-East of Paris Basin in order to define the geometry of the Dogger and Trias reservoirs. The goal of this work was to evaluate the possibilities of storage of CO2 in the deep saline aquifers of the Paris Basin. This paper presents a new updated vision of the structural map and geology of North-East of Paris Basin.The preliminary phase involved reprocessing of 343 oil seismic lines recorded between 1981 and 1988, adding up to 303 kilometres coming from 10 different surveys. The quality of the existing data was not always good and work was performed to digitize original bands. Data consistency at the different scale was also analysed and checked.Particular attention was applied to the faults of the Dogger and Trias reservoirs and all shallower structure and aquifers up to the surface. The whole set of available data was harmonized through the establishment of a model of static multi-layer correction of the tertiary cover and by the use of adapted deconvolution. The crossings are thus homogeneous knowing that in-depth quality and definition remain dependent on the parameters of recording on the ground and in particular the length of the maximum offset and the distance between traces.Interpretation made it possible to identify the reflectors from the establishment of synthetic seismograms on 3 representative wells. The tops of the following layers were picked: Cenomanian, Gault, Oxfordian, Dogger, Aalenian, medio liassic sandstones, Triassic sandstones, and the metamorphic basement. The structure issued by this interpretation is notably different from that presented by the public sources because of the different density of the profiles taken into account. Explanations of the different interpretations are discussed in the paper. The isochrone maps were converted in-depth on the basis of 38 calibrations per well to illustrate the interpretation.The different layers show smooth deformations but also some faults where continuity and density increases with the depth because of the character inherited from the fault in the basement.Accidents visible are not continuous from the top of Cenomanian and to the top of the Gault, rather they correspond to the fault of Pays de Bray oriented N130 ° and to a meridian accident located in the western part of the study. From the top of Oxfordian, the continuity increases for these accidents. In addition, some oriented North-South faults appear. All the major faults are visible from the Sandstones in Medio Liasic. In addition to antithetic faults in relation with the accidents previously described, other meridian faults appear in the North of the fault of Pays de Bray.It should be indicated uncertainties in the picking of reflectors between the Trias and the basement, many multiples resistant to the processing programs interfering with these events.This project is based on an appropriated density of existing seismic 2D lines. The unequal quality of these acquisitions makes it possible to define structural aspects of the deep layers but does not allow to image possible lateral variations of rock types of the reservoir.
    Energy Procedia 12/2011; 4:4607-4616. DOI:10.1016/j.egypro.2011.02.420
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fulminant hepatic failure is a severe clinical syndrome associated with a high rate of patient mortality. Recent studies have shown that in addition to its hematopoietic effect, erythropoietin (EPO) has multiple protective effects and exhibits antiapoptotic, antioxidant and anti‑inflammatory activities. The present study aimed to determine the hepatoprotective effect of EPO and to elucidate the underlying mechanisms using a D‑galactosamine (D‑GalN)/lipopolysaccharide (LPS)‑induced model of acute liver injury. Experimental groups of mice were administered with various doses of EPO (1,000, 3,000 or 10,000 U/kg, intraperitoneal) once per day for 3 days, prior to injection with D‑GalN (700 mg/kg)/LPS (10 µg/kg). Mice were sacrificed 8 h after treatment with D‑GalN/LPS. Liver function and histopathology, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px) activities and EPO receptor (EPOR) and phosphatidylinositol 3‑kinase (PI3K) mRNA expression were evaluated. D‑GalN/LPS administration markedly induced liver injury, as evidenced by elevated levels of serum aminotransferases, as well as histopathological changes. Compared with the D‑GalN/LPS group, pretreatment with EPO significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase and MDA, and increased the activities of SOD and GSH‑Px. Furthermore, the protective effects of EPO were paralleled by an upregulation in the mRNA expression of EPOR and PI3K. These data suggest that EPO can ameliorate D‑GalN/LPS‑induced acute liver injury by reducing oxidative stress and upregulating the mRNA expression of EPOR and PI3K.
    Molecular Medicine Reports 04/2014; 10(1). DOI:10.3892/mmr.2014.2164 · 1.48 Impact Factor