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Mutagenic Assessment of Olmesartan Cilexetil by Bacterial Mutation Assay.

Ji Won KIM ; Ilyoung AHN ; Sung Ha RYU ; Hong Ryeol JEON ; Bong Sang LEE ; Kyu Bong KIM

Toxicological Research.2013;29(3):217-219.

Hypertension is a serious health problem due to high frequency and concomitant other diseases including cardiovascular and renal dysfunction. Olmesartan cilexetil is a new antihypertensive drug associated with angiotensin II receptor antagonist. This study was conducted to evaluate the mutagenicity of olmesartan cilexetil by bacterial reverse mutation test using Salmonella typhimurium (TA100, TA1535, TA98, and TA1537) and Escherichia coli (WP2 uvrA). At the concentrations of 0, 62, 185, 556, 1667, and 5000 microg/plate, olmesartan cilexetil was negative in both Salmonella typhimurium and Escherichia coli regardless of presence or absence of metabolic activation system (S9 mix). These results demonstrate that olmesartan cilexetil does not induce bacterial reverse mutation.
Biotransformation ; Escherichia coli ; Hypertension ; Imidazoles ; Receptors, Angiotensin ; Salmonella typhimurium ; Tetrazoles

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Investigation of Water Safety in Non-treated Drinking Water with Trace Toxic Metals.

Suw Young LY ; Dae Hong KIM ; Ga Eun LEE

Toxicological Research.2013;29(3):211-215.

The trace toxic metal copper was assayed using mercury immobilized on a carbon nanotube electrode (MCW), with a graphite counter and a reference electrode. In this study, a macro-scale convection motor was interfaced with a MCW three-electrode system, in which a handmade MCW was optimized using cyclic-and square-wave stripping voltammetry. An analytical electrolyte for tap water was used instead of an expensive acid or base ionic solution. Under these conditions, optimum parameters were 0.09 V amplitude, 40 Hz frequency, 0.01 V incremental potential, and a 60-s accumulation time. A diagnostic working curve was obtained from 50.0 to 350 microg/L. At a constant Cu(II) concentration of 10.0 microg/L, the statistical relative standard deviation was 1.78% (RSD, n = 15), the analytical accumulation time was only 60 s, and the analytical detection limit approached 4.6 microg/L (signal/noise = 3). The results were applied to non-treated drinking water. The content of the analyzed copper using 9.0 and 4.0 microg/L standards were 8.68 microg/L and 3.96 microg/L; statistical values R2 = 0.9987 and R2 = 0.9534, respectively. This method is applicable to biological diagnostics or food surveys.
Convection ; Copper ; Diagnosis ; Drinking Water* ; Drinking* ; Electrodes ; Graphite ; Limit of Detection ; Metals* ; Nanotubes, Carbon ; Organothiophosphorus Compounds ; Reference Standards ; Drinking Water

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Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of epsilon-Acetamidocaproic Acid in Rat Plasma.

Tae Hyun KIM ; Yong Seok CHOI ; Young Hee CHOI ; Yoon Gyoon KIM

Toxicological Research.2013;29(3):203-209.

A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of epsilon-acetamidocaproic acid (AACA), the primary metabolite of zinc acexamate (ZAC), in rat plasma by using normetanephrine as an internal standard. Sample preparation involved protein precipitation using methanol. Separation was achieved on a Gemini-NX C18 column (150 mm x 2.0 mm, i.d., 3 microm particle size) using a mixture of 0.1% formic acid-water : acetonitrile (80 : 20, v/v) as the mobile phase at a flow rate of 200 microl/min. Quantification was performed on a triple quadrupole mass spectrometer employing electrospray ionization and operating in multiple reaction monitoring (MRM) and positive ion mode. The total chromatographic run time was 4.0 min, and the calibration curves of AACA were linear over the concentration range of 20~5000 ng/ml in rat plasma. The coefficient of variation and relative error at four QC levels were ranged from 1.0% to 5.8% and from -8.4% to 6.6%, respectively. The present method was successfully applied for estimating the pharmacokinetic parameters of AACA following intravenous or oral administration of ZAC to rats.
6-Aminocaproic Acid ; Acetonitriles ; Administration, Oral ; Animals ; Calibration ; Mass Spectrometry* ; Methanol ; Normetanephrine ; Pharmacokinetics ; Plasma* ; Rats* ; Zinc

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Anti-inflammatory Effect of Isaria sinclairii Glycosaminoglycan in an Adjuvant-treated Arthritis Rat Model.

Mi Young AHN ; Sang Duck JEE ; Jae Sam HWANG ; Eun Young YUN ; Kwang Seok AHN ; Yeong Shik KIM

Toxicological Research.2013;29(3):195-201.

The anti-inflammatory effects of glycosaminoglycan (GAG) derived from Isaria sinclairii (IS) and of IS extracts were investigated in a complete Freund's adjuvant (CFA)-treated chronic arthritis rat model. Groups of rats were treated orally with 30 mg/kg one of the following: [1] saline control, extracts of [2] water-IS, [3] methanol-IS, [4] butanol-IS, [5] ethyl acetate-IS, or [6] Indomethacin(R) as the positive control for a period of two weeks. The anti-paw edema effects of the individual extracts were in the following order: water-IS ex. > methanol ex. > butanol ex. > ethyl acetate ex. The water/methanol extract from I. sinclairii remarkably inhibited UV-mediated upregulation of NF-kappaB activity in transfected HaCaT cells. GAG as a water-soluble alcohol precipitated fraction also produced a noticeable anti-edema effect. This GAG also inhibited the pro-inflammatory cytokine levels of prostaglandin E2-stimulated lipopolysaccharide in LAW 264.7 cells, cytokine TNF-alpha production in splenocytes, and atherogenesis cytokine levels of vascular endothelial growth factor (VEGF) production in HUVEC cells in a dose-dependent manner. In the histological analysis, the LV dorsal root ganglion, including the articular cartilage, and linked to the paw-treated IS GAG, was repaired against CFA-induced cartilage destruction. Combined treatment with Indomethacin(R) (5 mg/kg) and IS GAG (10 mg/kg) also more effectively inhibited CFA-induced paw edema at 3 hr, 24 hr, and 48 hr to levels comparable to the anti-inflammatory drug, indomethacin. Thus, the IS GAG described here holds great promise as an anti-inflammatory drug in the future.
Acetates ; Animals ; Arthritis* ; Atherosclerosis ; Cartilage ; Cartilage, Articular ; Edema ; Freund's Adjuvant ; Ganglia, Spinal ; Human Umbilical Vein Endothelial Cells ; Indomethacin ; Inflammation ; Jurisprudence ; Methanol ; NF-kappa B ; Rats* ; Tumor Necrosis Factor-alpha ; Up-Regulation ; Vascular Endothelial Growth Factor A

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Hepatotoxicity in Rats Treated with Dimethylformamide or Toluene or Both.

Ki Woong KIM ; Yong Hyun CHUNG

Toxicological Research.2013;29(3):187-193.

The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione-S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of N-methylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.
Animals ; Body Weight ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System ; Dimethylformamide* ; Formamides ; Glutathione Peroxidase ; Lipid Peroxides ; Liver ; Olea ; Plant Oils ; Rats* ; Solvents ; Toluene* ; Veins ; Olive Oil

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Aluminum Nanoparticles Induce ERK and p38MAPK Activation in Rat Brain.

Jung Taek KWON ; Gyun Baek SEO ; Eunhye JO ; Mimi LEE ; Hyun Mi KIM ; Ilseob SHIM ; Byung Woo LEE ; Byung Il YOON ; Pilje KIM ; Kyunghee CHOI

Toxicological Research.2013;29(3):181-185.

Aluminum nanoparticles (Al-NPs) are one of the most widely used nanomaterial in cosmetics and medical materials. For this reason, Al-NP exposure is very likely to occur via inhalation in the environment and the workplace. Nevertheless, little is known about the mechanism of Al-NP neurotoxicity via inhalation exposure. In this study, we investigated the effect AL-NPs on the brain. Rats were exposed to Al-NPs by nasal instillation at 1 mg/kg body weight (low exposure group), 20 mg/kg body weight (moderate exposure group), and 40 mg/kg body weight (high exposure group), for a total of 3 times, with a 24-hr interval after each exposure. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated that the presence of aluminum was increased in a dose-dependent manner in the olfactory bulb (OFB) and the brain. In microarray analysis, the regulation of mitogen-activated protein kinases (MAPK) activity (GO: 0043405), including Ptprc, P2rx7, Map2k4, Trib3, Trib1, and Fgd4 was significantly over-expressed in the treated mice than in the controls (p = 0.0027). Moreover, Al-NPs induced the activation of ERK1 and p38 MAPK protein expression in the brain, but did not alter the protein expression of JNK, when compared to the control. These data demonstrate that the nasal exposure of Al-NPs can permeate the brain via the olfactory bulb and modulate the gene and protein expression of MAPK and its activity.
Aluminum* ; Animals ; Body Weight ; Brain* ; Inhalation ; Inhalation Exposure ; Mass Spectrometry ; Mice ; Microarray Analysis ; Mitogen-Activated Protein Kinases ; Nanoparticles* ; Nanostructures ; Olfactory Bulb ; p38 Mitogen-Activated Protein Kinases ; Plasma ; Rats*

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Gastrointestinal Tract Abnormalities Induced by Prenatal Valproic Acid Exposure in Rat Offspring.

Ji Woon KIM ; Chang Soon CHOI ; Ki Chan KIM ; Jin Hee PARK ; Hana SEUNG ; So Hyun JOO ; Sung Min YANG ; Chan Young SHIN ; Seung Hwa PARK

Toxicological Research.2013;29(3):173-179.

In-utero exposure to valproic acid (VPA) has been known as a potent inducer of autism spectrum disorder (ASD), not only in humans, but also in animals. In addition to the defects in communication and social interaction as well as repetitive behaviors, ASD patients usually suffer from gastrointestinal (GI) problems. However, the exact mechanism underlying these disorders is not known. In this study, we examined the gross GI tract structure and GI motility in a VPA animal model of ASD. On embryonic day 12 (E12), 4 pregnant Sprague-Dawley (SD) rats were subcutaneously injected with VPA (400 mg/kg) in the treatment group, and with phosphate buffered saline (PBS) in the control group; the resulting male offspring were analyzed at 4 weeks of age. VPA exposure decreased the thickness of tunica mucosa and tunica muscularis in the stomach and ileum. Other regions such as duodenum, jejunum, and colon did not show a significant difference. In high-resolution microscopic observation, atrophy of the parietal and chief cells in the stomach and absorptive cells in the ileum was observed. In addition, decreased staining of the epithelial cells was observed in the hematoxylin and eosin (H&E)-stained ileum section. Furthermore, decreased motility in GI tract was also observed in rat offspring prenatally exposed to VPA. However, the mechanism underlying GI tract defects in VPA animal model as well as the association between abnormal GI structure and function with ASD is yet to be clearly understood. Nevertheless, the results from the present study suggest that this VPA ASD model undergoes abnormal changes in the GI structure and function, which in turn could provide beneficial clues pertaining to the pathophysiological relevance of GI complications and ASD phenotypes.
Animals ; Atrophy ; Child ; Autism Spectrum Disorder ; Colon ; Duodenum ; Eosine Yellowish-(YS) ; Epithelial Cells ; Gastrointestinal Tract* ; Hematoxylin ; Humans ; Ileum ; Interpersonal Relations ; Jejunum ; Male ; Models, Animal ; Mucous Membrane ; Phenotype ; Rats* ; Stomach ; Valproic Acid*

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Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection.

Sang Il GUM ; Min Kyung CHO

Toxicological Research.2013;29(3):165-172.

Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection.
Acetaminophen* ; Biological Agents ; Glutathione ; Liver Failure ; Metabolism ; Mortality ; Pharmacokinetics

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Loss of Integrity: Impairment of the Blood-brain Barrier in Heavy Metal-associated Ischemic Stroke.

Jeong Hyeon KIM ; Hyeong Min BYUN ; Eui Cheol CHUNG ; Han Young CHUNG ; Ok Nam BAE

Toxicological Research.2013;29(3):157-164.

Although stroke is one of the leading causes of death and disability worldwide, preventive or therapeutic options are still limited. Therefore, a better understanding of the pathophysiological characteristics of this life-threatening disease is urgently needed. The incidence and prevalence of ischemic stroke are increased by exposure to certain types of xenobiotics, including heavy metals, suggesting the possible toxicological contribution of these compounds to the onset or aggravation of stroke. Among the potential targets, we have focused on alterations to cerebral endothelial cells (CECs), which play important roles in maintaining the functional integrity of brain tissue.
Blood-Brain Barrier* ; Brain ; Cause of Death ; Endothelial Cells ; Incidence ; Metals, Heavy ; Prevalence ; Stroke* ; Tight Junctions ; Xenobiotics

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Structural Aspects of GPCR-G Protein Coupling.

Ka Young CHUNG

Toxicological Research.2013;29(3):149-155.

G protein-coupled receptors (GPCRs) are membrane receptors; approximately 40% of drugs on the market target GPCRs. A precise understanding of the activation mechanism of GPCRs would facilitate the development of more effective and less toxic drugs. Heterotrimeric G proteins are important molecular switches in GPCR-mediated signal transduction. An agonist-activated receptor interacts with specific sites on G proteins and promotes the release of GDP from the Galpha subunit. Because of the important biological role of the GPCR-G protein coupling, conformational changes in the G protein upon receptor coupling have been of great interest. One of the most important questions was the interface between the GPCR and G proteins and the structural mechanism of GPCR-induced G protein activation. A number of biochemical and biophysical studies have been performed since the late 80s to address these questions; there was a significant breakthrough in 2011 when the crystal structure of a GPCR-G protein complex was solved. This review discusses the structural aspects of GPCR-G protein coupling by comparing the results of previous biochemical and biophysical studies to the GPCR-G protein crystal structure.
GTP-Binding Proteins ; Guanosine Diphosphate ; Heterotrimeric GTP-Binding Proteins ; Membranes ; Signal Transduction

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