Comparative toxicity of nonsteroidal anti-inflammatory agents

Abbreviations: AA, arachidonic acid; DHA, docosahexaenoic acid; EMSA, electrophoretic mobility-shift assay; EPA, eicosapentaenoic acid; FA, fatty acid; FCS, fetal calf serum; LA, linoleic acid; LPL, lipoprotein lipase; MTP, mitochondrial transmembrane potential; NEFA, non-esterified FA; OA, oleic acid; PA, palmitic acid; PI, propidium iodide; PPAR, peroxisome-proliferator-activated receptor; PS, phosphatidylserine; PTP, permeability transition pore; ROS, reactive oxygen species; RXR, retinoid X receptor; SA, stearic acid; TAG, triacylglycerol

2-Hydroxy-1,4-naphthoquinone has previously been shown to cause severe haemolytic anaemia and renal tubular necrosis in animals. In order to establish if such toxic effects are common to other 2-hydroxynaphthoquinone derivatives, the short-term toxicity of a number of 2-hydroxy-3-alkyl-1,4-naphthoquinones has been compared in rats. 2-Hydroxy-3-methyl, 2-hydroxy-3-ethyl- and 2-hydroxy-3-propyl-1,4-naphthoquinone were found to cause both haemolysis and renal damage, although the severity of the changes provoked by these substances was much lower than those induced by the parent compound at an equivalent dose-level. Furthermore, the toxicity of the hydroxy-alkylnaphthoquinones decreased with increasing size of the alkyl substituent and no toxic changes were recorded in animals dosed with 2-hydroxy-3-butyl- or 2-hydroxy-3-pentyl-1,4-naphthoquinone. The relationship between the in vivo effects of these substances and previously reported data on their in vitro cytotoxicity is discussed in relation to the mechanism of toxicity of these and other naphthoquinone derivatives.

In-Chul Lee, 1 Je-Won Ko, 1 Sung-Hyeuk Park, 1 Je-Oh Lim, 1 In-Sik Shin, 1 Changjong Moon, 1 Sung-Hwan Kim, 2 Jeong-Doo Heo, 3 Jong-Choon Kim 1

1 College of Veterinary Medicine BK21 Plus Project Team, Chonnam National University, Gwangju, 2 Jeonbuk Department of Inhalation Research, Korea Institute of Toxicology, Jeongeup, 3 Gyeongnam Department of Environment and Toxicology, Korea Institute of Toxicology, Gyeongnam, Republic of Korea

Abstract: Despite widespread use and prospective biomedical applications of copper nanoparticles (Cu NPs), their biosafety issues and kinetics remain unclear. Thus, the aim of this study was to compare the detailed in vivo toxicity of Cu NPs and cupric ions (CuCl 2 ; Cu ions) after a single oral dose. We determined the physicochemical characteristics of Cu NPs, including morphology, hydrodynamic size, zeta potential, and dissolution in gastric (pH ), vehicle (pH ), and intestinal (pH ) conditions. We also evaluated the kinetics of Cu following a single equivalent dose (500 mg/kg) of Cu NPs and Cu ions. Cu NPs had highest dissolution (%) only in gastric conditions when compared with complete dissolution of Cu ions under various physiological milieus. Kinetic analysis revealed that highest Cu levels in blood and tested organs of Cu NP-treated rats were 15%–25% lower than that of Cu ions. Similar to the case of Cu ions, Cu levels in the tested organs (especially liver, kidney, and spleen) of Cu NP-treated rats increased significantly when compared with the vehicle control. However, delay in reaching the highest level and biopersistence of Cu were observed in the blood and tested organs of Cu NP-treated rats compared with Cu ions. Extremely high levels of Cu in feces indicated that unabsorbed Cu NPs or absorbed Cu ions were predominantly eliminated through liver/feces. Cu NPs exerted apparent toxicological effects at higher dose levels compared with Cu ions and showed sex-dependent differences in mortality, biochemistry, and histopathology. Liver, kidney, and spleen were the major organs affected by Cu NPs. Collectively, the toxicity and kinetics of Cu NPs are most likely influenced by the release of Cu dissociated from Cu NPs under physiological conditions.

Keywords: copper nanoparticles, cupric ions, comparative toxicity, toxicokinetics
 

Comparative toxicity of nonsteroidal anti-inflammatory agents

comparative toxicity of nonsteroidal anti-inflammatory agents

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comparative toxicity of nonsteroidal anti-inflammatory agentscomparative toxicity of nonsteroidal anti-inflammatory agentscomparative toxicity of nonsteroidal anti-inflammatory agentscomparative toxicity of nonsteroidal anti-inflammatory agentscomparative toxicity of nonsteroidal anti-inflammatory agents