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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Journal DOI :
The Korean Society of Toxicology
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Volume & Issues
Volume 26, Issue 4 - Dec 2010
Volume 26, Issue 3 - Sep 2010
Volume 26, Issue 2 - Jun 2010
Volume 26, Issue 1 - Mar 2010
Selecting the target year
Applications of Genetically Modified Tools to Safety Assessment in Drug Development
Kay, Hee-Yeon ; Wu, Hong-Min ; Lee, Seo-In ; Kim, Sang-Geon ;
Toxicological Research, volume 26, issue 1, 2010, Pages 1~8
DOI : 10.5487/TR.2010.26.1.001
The process of new drug development consists of several stages; after identifying potential candidate compounds, preclinical studies using animal models link the laboratory and human clinical trials. Among many steps in preclinical studies, toxicology and safety assessments contribute to identify potential adverse events and provide rationale for setting the initial doses in clinical trials. Gene modulation is one of the important tools of modern biology, and is commonly employed to examine the function of genes of interest. Advances in new drug development have been achieved by exploding information on target selection and validation using genetically modified animal models as well as those of cells. In this review, a recent trend of genetically modified methods is discussed with reference to safety assessments, and the exemplary applications of gene-modulating tools to the tests in new drug development were summarized.
Assessment of the Dermal and Ocular Irritation Potential of Lomefloxacin by Using In Vitro Methods
Ahn, Jun-Ho ; Eum, Ki-Hwan ; Lee, Mi-Chael ;
Toxicological Research, volume 26, issue 1, 2010, Pages 9~14
DOI : 10.5487/TR.2010.26.1.009
The evaluation of eye and skin irritation potential is essential to ensuring the safety of human in contact with a wide variety of substances. Despite this importance of irritation test, little is known with respect to the irritation potency of lomefloxacin, a fluoroquinolone antibiotic, which has been known to cause phototoxicity with an abnormal reaction of the skin. Thus, to investigate the tendency of lomefloxacin to cause eye and skin irritation, we carried out in vitro eye irritation test using Balb/c 3T3, and in vitro skin irritation test using
human skin model system. 3T3 neutral red uptake assay has been proposed as a potential replacement alternative for the Draize Eye irritation test. In this study, the
value obtained for lomefloxacin was 375
. According to the classification model used for determining in vitro categories, lomefloxacin was classified as moderately irritant. For evaluation of skin irritation, engineered epidermal equivalents (
) were subjected to 10 and 25 mg of lomefloxacin for 15 minutes. Tissue damage was assessed by tissue viability evaluation, and by the release of a pro-inflammatory mediator, interleukin- 1
. Lomefloxacin increased the interleukin-1
release after 15 minutes of exposure and 42 hours of post incubation, although no decrease in viability was observed. Therefore, lomefloxacin is considered to be moderately irritant to skin and eye.
Identification of Differentially Expressed Genes in Human Mesenchymal Stem Cell-Derived Neurons
Heo, Ji-Hye ; Cho, Kyung-Jin ; Choi, Dal-Woong ; Kim, Suhng-Wook ;
Toxicological Research, volume 26, issue 1, 2010, Pages 15~19
DOI : 10.5487/TR.2010.26.1.015
Mesenchymal stem cells (MSCs) have greater potential for immediate clinical and toxicological applications, due to their ability to self-renew, proliferate, and differentiate into a variety of cell types. To identify novel candidate genes that were specifically expressed during transdifferentiation of human MSCs to neuronal cells, we performed a differential expression analysis with random priming approach using annealing control primer-based differential display reverse transcription-polymerase chain reaction approach. We identified genes for acyl-CoA thioesterase, tissue inhibitor of metalloproteinases-1, brain glycogen phosphorylase, ubiquitin C-terminal hydrolase and aldehyde reductase were up-regualted, whereas genes for transgelin and heparan sulfate proteoglycan were down-regulated in MSC-derived neurons. These differentially expressed genes may have potential role in regulation of neurogenesis. This study could be applied to environmental toxicology in the field of testing the toxicity of a chemical or a physical agent.
Gene Expression Analysis of So Called Asian Dust Extracts in Human Acute Myeloid Leukemia Cells
Choi, You-Jin ; Yin, Hu-Quan ; Park, Eun-Jung ; Park, Kwang-Sik ; Kim, Dae-Seon ; Lee, Byung-Hoon ;
Toxicological Research, volume 26, issue 1, 2010, Pages 21~28
DOI : 10.5487/TR.2010.26.1.021
As the frequency and the intensity of so called Asian dust (AD) events have increased, public concerns about the adverse health effects has spiked sharply over the last two decades. Despite the recent reports on the correlation between AD events and the risk for cardiovascular and respiratory disease, the nature of the toxicity and the degree of the risk are yet largely unknown. In the present study, we investigated the effects of the dichloromethane extract of AD (AD-X) and that of urban dust (NAD-X) collected during a non-AD period on gene expression in HL-60 cells using Illumina Sentrix HumanRef-8 Expression BeadChips. Global changes in gene expression were analyzed after 24 h of incubation with 50 or 100
/ml AD-X and NAD-X. By one-way analysis of variance (p < 0.05) and Benjamini-Hochberg multiple testing correction for false discovery rate of the results, 573 and 297 genes were identified as AD-X- and NAD-X-responsive, respectively. The genes were classified into three groups by Venn diagram analysis of their expression profile, i.e., 290 AD-X-specific, 14 NAD-X-specific, and 283 overlapping genes. Quantitative realtime PCR confirmed the changes in the expression levels of the selected genes. The expression patterns of five genes, namely SORL1, RABEPK, DDIT4, AZU1, and NUDT1 differed significantly between the two groups. Following rigorous validation process, these genes may provide information in developing biomarker for AD exposure.
Antimutagenic and Anticarcinogenic Effect of Methanol Extracts of Sweetpotato (Ipomea batata) Leaves
Kang, Hwan-Goo ; Jeong, Sang-Hee ; Cho, Joon-Hyoung ;
Toxicological Research, volume 26, issue 1, 2010, Pages 29~35
DOI : 10.5487/TR.2010.26.1.029
The present study was conducted to investigate the antimutagenic potential of the methanolic extract from the leaves of sweet potato (Ipomea batatas, IB) with the SOS chromotest (umu test) and Salmonella typhimurium TA 98 and TA 100. The anticarcinogenic effects were also studied by calculation of the
on human cancer cell lines and investigating the function of gap junction in rat liver epithelial cells. The IB extract inhibited dose-dependently the
-galactosidase activity induced spontaneously at concentration of more than 200 mg/ml in S. typhimurium TA 1535/pSK 1002, and decreased significantly (p < 0.01) the
-galactosidase activities induced by mutagen 6-chloro-9-[3-(2-chloroethylamino)proylamino]-2-methoxyacridine dihydrochloride (ICR) at dose of more than 0.4 mg/0.1 ml. The IB extract showed no effect on the spontaneous reversions of S. typhimurium TA 98 and 100 but benzo(
)pyrene (BaP)-stimulated reversions were decreased dose-dependently (p < 0.01) at the concentration of more than 100 mg/ml. The
value of stomach cancer cells was lower than that of normal rat liver epithelial cells, but the values of colon and uterine cancer cell lines were similar to those of normal rat liver epithelial cells. The transfer of dye through gap junctions was not affected by treatment of the IB extracts at any concentration during treatment periods. The simultaneously treatment of IB extract and 12-O-tetradecanoylphorbol-13-acetate (TPA) effectively prevented the inhibition of dye transfer induced by TPA 1 hour after treatment at all exposed concentrations. The number of gap junctions was significantly (p < 0.01) increased by the treatment with IB extract at concentrations of more than 40
/ml. The inhibition of the expression of gap junction proteins by TPA (0.01
/ml) was recovered dose dependently by the simultaneous treatment of IB extracts. Our data suggest that Ipomea batatas has antimutagenic and anticarcionogenic activity in vitro.
Methanolic Extract of Asterina pectinifera inhibits LPS-Induced Inflammatory Mediators in Murine Macrophage
Jo, Wol-Soon ; Choi, Yoo-Jin ; Kim, Hyoun-Ji ; Nam, Byung-Hyouk ; Lee, Gye-An ; Seo, Su-Yeong ; Lee, Sang-Wha ; Jeong, Min-Ho ;
Toxicological Research, volume 26, issue 1, 2010, Pages 37~46
DOI : 10.5487/TR.2010.26.1.037
This study aimed to elucidate anti-inflammatory activities from extracts of Asterina pectinifera on nitric oxide (NO) production, TNF-
and IL-6 release in lipopolysaccharide (LPS)-stimulated murine macrophage cell, RAW264.7. We prepared the methanolic extracts (60-MAP, 70-MAP, 80-MAP and 90-MAP), aqueous extract (W-AP) and functional bioactive compound fraction (He-AP and EA-AP) from Asterina pectinifera according to extract method. The 60-MAP, 70-MAP, 80-MAP, 90-MAP and W-AP were significantly suppressed LPS-induced production NO, TNF-
and IL-6 secretion in a concentration-dependent manner (P < 0.05). Especially, 80-MAP by extracted 80% methanol had the strongest activity in reduction of inflammatory mediators among these extracts. Indeed, to identify active fraction, which contained potential bioactive compounds, from 80-MAP of Asterina pectinifera, we tested anti-inflammatory activity of the He-AP or the EA-AP. The He-AP was next extracted from 80-MAP and the EA-AP were extracted from the other methanol layer except the He-AP. The EA-AP demonstrated a strong anti-inflammatory effect through its ability to reduce NO production and it also inhibited the production of proinflammatory cytokines such as IL-6 and TNF-
at low concentration. These results suggested that the methanolic extract from Asterina pectinifera had the potential inhibitory effects on the production of these inflammatory mediators.
Cloning and Expression in Pichia pastoris of a New Cytochrome P450 Gene from a Dandruff-causing Malassezia globosa
Lee, Eun-Chang ; Ohk, Seul-Ong ; Suh, Bo-Young ; Park, Na-Hee ; Kim, Beom-Joon ; Kim, Dong-Hak ; Chun, Young-Jin ;
Toxicological Research, volume 26, issue 1, 2010, Pages 47~52
DOI : 10.5487/TR.2010.26.1.047
The Malassezia fungi are responsible for various human skin disorders including dandruff and seborrheic dermatitis. Of the Malassezia fungi, Malassezia globosa (M. globosa) is one of the most common in human scalp. The completed genome sequence of M. globosa contains four putative cytochrome P450 genes. To determine the roles of Malassezia P450 enzymes in the biosynthesis of ergosterol, we isolated MGL3996 gene from M. globosa chromosomal DNA by PCR. The MGL3996 gene encodes an enzyme of 616 amino acids, which shows strong similarity with known CYP52s of other species. MGL3996 gene was cloned and expressed in Pichia pastoris (P. pastoris) heterologous yeast expression system. Using the yeast microsomes expressing MGL3996 protein, a typical P450 CO-difference spectrum was shown with absorption maximum at 448 nm. SDS-PAGE analysis revealed a protein band of apparent molecular weight 69 kDa and Western blot with anti-histidine tag antibody showed that MGL3996 was successfully expressed in P. pastoris. Cloning and expression of a new P450 gene is an important step to study the P450 monooxygenase system of M. globosa and to understand the role of P450 enzymes in pathophysiology of dandruff.
Mouse Single Oral Dose Toxicity Study of DHU001, a Polyherbal Formula
Roh, Seong-Soo ; Ku, Sae-Kwang ;
Toxicological Research, volume 26, issue 1, 2010, Pages 53~59
DOI : 10.5487/TR.2010.26.1.053
This study was conducted to obtain acute information of the oral dose toxicity of DHU001, a polyherbal formula in male and female mice. In order to calculated 50% lethal dose (
) and approximate lethal dose (LD), test material was once orally administered to male and female ICR mice at dose levels of 2000, 1000, 500, 250 and 0 (vehicle control) ml/kg (body weight). The mortality and changes on body weight, clinical signs, gross observation, organ weight and histopathology of principle organs were monitored 14 days after treatment with DHU001. We could not find any mortalities, DHU001 treatment-related clinical signs, changes on the body and organ weights, gross and histopathological findings. The results obtained in this study suggest that
and approximate LD in mice after single oral dose of DHU001 were considered over 2000 mg/kg in both female and male mice.
Safety Evaluation and Anti-wrinkle Effects of Retinoids on Skin
Kim, Bae-Hwan ;
Toxicological Research, volume 26, issue 1, 2010, Pages 61~66
DOI : 10.5487/TR.2010.26.1.061
Retinoids have many beneficial effects on dermatological applications. But, retinoids cause skin irritation. In this study, the safety of retinoids was clarified via both primary skin irritation test in rabbits and sensitization study using an integrated model for the differentiation of chemical-induced allergic and irritant skin reaction (IMDS), an alternative method to sensitization test. The effects of retinoids on the change of ultraviolet A (UVA)-induced matrix metalloproteinase-1 (MMP-1) in human skin fibroblasts and the modulation of type-1 pN collagen synthesis in hairless mice were examined to clarify the anti-wrinkle effects. Alltrans retinol (t-ROL) and its derivative, all-trans retinoic acid (t-RA), showed mild skin irritation but did not induce the sensitization. t-ROL and t-RA exerted anti-wrinkle effects by inhibiting the UVA-induced MMP-1 in human skin fibroblasts and increasing the type-1 pN collagen synthesis in hairless mice. These findings suggest that retinoids do not induce the allergy, and show anti-wrinkle effects by decreasing MMP-1 activation and increasing collagen synthesis.
Reproductive and Developmental Toxicity of Amitraz in Sprague-Dawley Rats
Lim, Jeong-Hyeon ; Kim, Sung-Hwan ; Kim, Kang-Hyeon ; Park, Na-Hyeong ; Shin, In-Sik ; Moon, Chang-Jong ; Park, Soo-Hyun ; Kim, Sung-Ho ; Kim, Jong-Choon ;
Toxicological Research, volume 26, issue 1, 2010, Pages 67~74
DOI : 10.5487/TR.2010.26.1.067
The present study was conducted to obtain information on the effects of amitraz on reproductive and developmental parameters in rats. The test chemical was administered via the drinking water containing 0, 40, 120, and 360 ppm to male rats from 2 weeks before mating to the end of 14-day mating period and to females from 2 weeks before mating, throughout mating, gestation and up to lactational day 4. During the study period, clinical signs, body weights, food intake, organ weights, reproductive and littering findings, necropsy findings, sperm parameters, and histopathology were examined. At 360 ppm, decreases in the body weight gain, food consumption, and the number of live pups and an increase in the post-implantation loss were observed. In addition, decreases in the seminal vesicle weight and sperm motility were found in males. At 120 ppm, a decrease in the food consumption was found transiently in both males and females, but no reproductive and developmental toxicity was observed in both sexes. There were no signs of either general or reproductive and developmental toxicity in the 40 ppm group. Based on these results, it was concluded that the repeated oral administration of amitraz to rats resulted in a decrease in the food consumption at 120 ppm and decreases in the seminal vesicle weight, sperm motility, and the number of live pups and an increase in the post-implantation loss at 360 ppm in rats. Under these experimental conditions, the no-observed-adverse-effect level (NOAEL) of amitraz for general and reproduction/developmental toxicity was believed to be 120 ppm, and the no-observed-effect level (NOEL) of amitraz was believed to be 40 ppm in rats.
Comparison of the Short Term Toxicity of Phthalate Diesters and Monoesters in Sprague-Dawley Male Rats
Kwack, Seung-Jun ; Han, Eun-Young ; Park, Jae-Seok ; Bae, Jung-Yun ; Ahn, Il-Young ; Lim, Seong-Kwang ; Kim, Dong-Hyun ; Jang, Dong-Eun ; Choi, Lan ; Lim, Hyun-Jung ; Kim, Tae-Hyung ; Patra, Nabanita ; Park, Kui-Lea ; Kim, Hyung-Sik ; Lee, Byung-Mu ;
Toxicological Research, volume 26, issue 1, 2010, Pages 75~82
DOI : 10.5487/TR.2010.26.1.075
This study was carried out to investigate the short term toxicity of nine phthalate diesters including di-2(ethylhexyl) phthalate (DEHP), di(n-butyl) phthalate (DBP), di-n-octyl phthalate (DnOP), diethyl phthalate (DEP), butylbenzyl phthalate (BBP), dimethyl phthalate (DMP), di-isodecyl phthalate (DIDP), diundecyl phthalate (DUP), and di-isononyl phthalate (DINP) and five phthalate monoesters including mono- (2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBuP), monobenzyl phthalate (MBeP), monoethyl phthalate (MEP), monomethyl phthalate (MMP) and phthalic acid (PA) in Sprague-Dawley male rats. Animals were administered 250 mg/kg/day (monoesters and PA) or 500 mg/kg/day (diesters) of phthalate for two weeks. All animals were examined for body and organ weights, blood hematology, serum biochemistry, and urine analysis. The body weight gain was significantly lower in rats treated with BBP, DBP, DINP, MEHP, MBuP, and PA than that of control. Liver weights were significantly increased in the DEHP, DBP, DnOP, DIDP, and MEHP groups as compared to the control group. Testes weights were significantly decreased only in the DEHP-, DnOP-, and DIDP-treated groups as compared to the control. Significant differences in hematological changes were not observed in any treatment groups. Significant increases in blood glucose levels were observed in the DEHP, MEHP, and MBeP groups. Aspartate aminotransferase (AST) levels were significantly increased in the DBP, DUP, DINP, MBuP, and MBeP groups, whereas alanine aminotransferase (ALT) levels were significantly increased only in the DEHP and MEHP groups. Serum ALP levels were significantly higher in phthalate diester (500 mg/kg/day)-treated rats as compared to control. However, the total cholesterol level was significantly reduced in the DEHP- and DIDP-treated groups, whereas serum triglyceride (TG) levels were higher in the DINP-, MEHP-, and MBuP-treated groups. These results suggest that short term toxicity of phthalate monoesters produces adverse effects as similar to phthalate diesters in Sprague-Dawley rats.