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The Korean Society of Toxicology
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Volume 15, Issue 1 - Mar 1999
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Effects of Oenanthe javanica Extracts on Mercury Accumulation in Organs of the Mouse
Toxicological Research, volume 15, issue 1, 1999, Pages 1~8
This study was performed to investigate the antitoxic effect of Oenanthe javanica extracts on orally administered mercury compound. Adult male ICR mice were exposed to methylmercuric chloride (CH3HgCl)through drinking water. The control, mercury treated and Oenanthe javanica treated groups not showed significant differences in mean body and organ weights of mice. The distribution of mercury in the cerebellum, kidney, liver and spleen of the mouse were examined according to a histochemical mathod. Grains of mercury traces were located in the purkinje cell and granular layers of the cerebellum and cortex of kidney respectively. Lesser staining of the grains was seen in the collecting tubules of medulla. in the liver, mercury accumulations were present primarily in the hepatocytes around portal area containing interlobular bile duct, artery and portal vein. Also grains of mercury traces were accumulated in the white pulp of the spleen. In the group of Oenanthe javanica extracts, staining intensity of mercury was decreased in the Purkinje cell layer of cerebellum and in the portal area of liver respectively. Staining patterns in kidney and spleen of extracts group were similar to that of only mercury treated group.
Four-Week Oral Toxicity Study of CJ-50002 (Vibrio Vaccine) in Rats
Toxicological Research, volume 15, issue 1, 1999, Pages 9~17
This study was performed to evaluate the subacute toxicity of CJ-50002 (Vibrio Vaccine) in SPF Spraqur-Dawley (SD) rats. Vibrio vaccine was administered orally at a dose level of high (167mg/kg/day), medium (16.7mg/kg/day), and low (16.7mg/kg/day) once a day and repeated fro 4 weeks. Ten males and female rats were assigned to each group. After 4 week administration, no significant dose-dependent changes in body weight, water and food consumption rate or organ weight were noted dependent changes in body weight, water and food consumption rate or organ weight were noted among 4 groups. Urinanalysis, hematology, and serum chemistry, also fail to detect any dose-related change among 4 groups tested. During necropsy and histopathological examination, no specific toxicity related to treated material was found. The result of this study demonstrated that vibrio vaccine when administered orally for 4 weeks at a high dose of 167mg/kg/day, no dose-related toxicity was found in treated make and female rats.
Differentiation Inducing Effect of (+)-Catechin in Human Leukemia HL60 Cells
Toxicological Research, volume 15, issue 1, 1999, Pages 19~25
(+)-Catechin inhibited the growth and induced the differentiation of HL-60 human leukimia cells. The degree of a differentiation by (+)-catechin during the differentiation, the expression assay, To understand the molecular mechanism of (+)-catechin during the differentiation, the expression level of oncogenes was detected by Northern blot analysis. c-Myc mRNA level was reduced after treatment with (+)-Catechin (10-4), however, the expression of c-jun was increased with a concentration dependent manner in HL-60 cells. These results showed that the differentiation and antiproliferation of HL-60 cells against (+)-Catechin was related to the reduction of c-myc and the induction of c-jun expression.
Effects of Different Intensities of Repeated Hypoxic Stress on Immune Functions in Mice
Toxicological Research, volume 15, issue 1, 1999, Pages 27~34
To study the nature of differentially manifested adaptive response of an organism according to the intensities of the stress, the immune effects of different levels of repeated hypoxia were investigated. Four experimental groups (NH : not -handled, 20% : handled, 15% or 10% : exposed to 15% or 10%
씨오투 with balanced nitrogen, respectively) of mice were exposed to different levels of hypoxia for 60 min/day, 5days/week in a repeated and intermittent manner. After 8 weeks' exposure to hypoxia environment, mice were subjected to immune function measurements, A decreased proportion of CD3+ CD8 phenotype cells in the study of splenocyte subsets was observed in the 10% group. Ovalbumin-stimulated IgG2a production was increased in the 15% group, while no changes were noted in the IgGl and IgM production. No significant changes of the antigen-stimulated splenocyte proliferation and the natural killer cell cytotoxicity were found. These results show that the stress effects on the immune systems can be varied according to the strength of the stress and that a mild level of repeated hypoxic stress can enhance the immune function of mice in this experimental model.
Recovery of RNA Synthesis After Ultraviolet Irradiation of Xeroderma Pigmentosum Group F and G
Toxicological Research, volume 15, issue 1, 1999, Pages 35~38
RNA synthesis rate was measured at different time points after UV irradiation in various xeroderma pigmentosum (XP) cells including complementation groups F and G. The RNA synthesis was assayed by measuring 3H-uridine incorporation. In normal cells, recovery of RNA synthesis was initiated at about 6 hr ager UV irradiation and reached to the same level as in unirradiated cells at 24hr after UV irradiation. By contrast, no such recovery was observed in group F,G XP cells.
Preventive Effects of Melatonin on the Cell-Mediated Immunotoxicity of Cadmium in ICR Mice
Kim, Young-Ok ; Cho, Dae-Hyun ; Chung, Hye-Joo ; Chung, Seung-Tae ; Kim, Jin-Ho ; Park, Jae-Hyun ; Kim, Joung-Hoon ; Ahn, Young-Keun ;
Toxicological Research, volume 15, issue 1, 1999, Pages 39~45
To investigate the preventive effects of melatonin (MLT) on the immunotoxicity of cadmium acetate[Cd(AC)2] in ICR mice, Mlt(10,50mg/kg as cadmium) were orally administered to mice once a day (5:00, PM) for 28 consecutive days. Cadmium(Cd) test solution was also administered at 25mg/kg of cadmium through the same route 2hr after administration of MLT daily, Mice were immunized and challenged with sheep red blood cells (SRBC). Immune functions evaluated were delayed type hypersensitivity (DTH) response, mitogenic response, and flow cytometry analysis. The results of these studies were summarized as follows ; DTH response was abnormally increased in mice treated with Cd alone. DTH response was normally depressed in mice treated with Cd plus MLT along with the increase of MLT doses. The mitogenic response of splenic T cell to Con A and that of B cells to LPS was remarkably increased by MLT treatment as compared with treatment of Cd alone In case of CD 8+ cells, the slight increase was observed in MLT treatment. Splenic T cells and B cells were significantly increased by MLT treatment as compared with treatment with Cd alone. These results suggest that MLT has significant preventive effects on the immunotoxic status induced by Cd exposure.
Effects of Methidathion on Humoral Immune Response in Mice
Toxicological Research, volume 15, issue 1, 1999, Pages 47~53
The effects of methidathion on humoral immune response were studied in BALB/c mice. 0.5 or 5.0 mg/kg/day methidathion were administered orally for 14 days. The parameters examined to assess apparent toxicity of methidathion included changes of body weight, relative weight of spleen, thymus, sidney and liver, and viable spllenic cell numbers. To evaluate the humoral immune response, thymus, kidney and liver, and viable splenic cell numbers. To evaluate the humoral immune resopnse, the plaque forming cell(PFC) responses sheep the red blood cells (SRBC) and the lovels of serum IgG to hen egg lysozyme (HEL) were determined. No alterations were observed in changes of body weights, relative organ weights and the numbers of viable splenocytes by exposure to any dose of methidathion. At the dose of 0.5mg/kg only PFC response was decreased, whereas both PFC response and the level of serum IgG were decreased significantly at the dose of 5.0 mg/kg. These results indicate that exposure to methidathion may cause sup[pression of humoral immune reponse in mice without overt changed in lymphoid organ weight or viability of splenocytes.
Four-Week Oral Toxicity Studies of CJ-50002 (Vibrio Vaccine) in Beagle Dogs
Toxicological Research, volume 15, issue 1, 1999, Pages 55~63
This study was carried out to investigate the four-week oral toxicity of the CH-50002 (Vibril vaccine) in beagle dogs. The beagle dogs were orally administered for 28 days, with dosage of 0.5, 5, 50 mg/kg/day, respectively. Animals treated with CJ-50002(Vibrio Vaccine) did not cause any death and show any clinical signs. There were not significantly different from the control group in urinalysis, ocular examination, hematological, serum biochemical value and histopathological examination. Therefore, CJ-50002(Vibrio Vaccine) was not indicated to have any toxic efent in the beagle dogs, when ti was orally administered below the dosage 50mg/kg/day for rour weeks.
Evaluation of Subcutaneous and Intramuscular Irritation of the Typhoid Vaccine in Rabbits
Ihm, Jong-Hee ; Che, Jeong-Hwan ; Li, Guang-Xun ; Kang, Byeong-Cheol ;
Toxicological Research, volume 15, issue 1, 1999, Pages 65~68
A newly developed typhoid vaccine was tested for subcutaneous and intramuscular irritationin male Ner Zealand White rabbits. In subcutaneous and intramuscular irritation tests, there were no observed clinical signs, body weight changes and gross pathologic findings at doses of 1 mg/ml and 0.0125 mg/ml during experimental period. However, in positive control (0.75% acetic acid), we could find various lesions that had hemorrhage, necrosis and infiltration of inflammation cells in both subcutaneous and muscular tissues. From these results, we suggest that typhoid vaccine is not irritant in subcutaneous and muscular tissue of rabbits.
Acute Intramuscular Toxicity Study of Typhoid Vaccine in Rats and Beagle Dogs
Lee, Won-Woo ; Che, Jeong-Hwan ; Li, Guang-Xum ; Kang, Byeong-Cheol ; Ihm, Jong-Hee ; Jun ;
Toxicological Research, volume 15, issue 1, 1999, Pages 69~73
Acute toxicity of typhoid vaccine was investigated using Sprague-Dawley (SD) rats and beagle dogs. SD rats and beagle dogs were administered intramuscularly with dosages of 0,. 0.2, 0.1, 0.05 and 0.025 mg/kg, respectively. In animals administered with typhoid vaccine, there were neither dead animals nor significant changes of body weights. In addition, no differences were found between control and treated groups in clinical signs and autopsy findings. Therefore, LD50 of typhoid vaccine was considered to be higher than 0.2 mg/kg in SD rats and beagle dogs.
Mutagenicity of Typhoid Vaccine
Li, Guang-Xun ; Kang, Byeong-Cheol ; Lee, Won-Woo ; Ihm, Jong-Hee ; Jung, Ji-Youn ; Lee, Yong-Soon ;
Toxicological Research, volume 15, issue 1, 1999, Pages 75~78
In order to evaluate the mutagenic potential of Typhoid vaccine, 3 sets of mutagenicity tests were performed. In the reverse mutation test using Salmonella typhimurium TA98, TA100, TA1535 and TA1537, Typhoid vaccine did not increase the number of revertant at the doses of 100, 50, 25, 12.5, 6.25
/plate. I n chromosome aberration analysis using CHO cells were not found chromosomal aberration in different concentrations with or without metabolic activation at the doses of 0.25 mg/ml, 0.5mg/ml, 1mg/ml. In mouse micronucleus test, no significant increase in the occurrence of micronucleated polychromatic erythrocytes was observed in ICE male mice intramuscularly administered with Typhoid vaccine at the dosed of 0.1 mg/ml, 0.5 mg/ml, 1mg/ml. These results indicate that Typhoid vaccine gas no mutagenic potential in these in vitro and in vivo systems.
Effects on Mammalian Tissues and Cells by Sulfur Containing Compounds
Toxicological Research, volume 15, issue 1, 1999, Pages 79~87
To know the stress response and antioxidative effect of sulfur containing compounds, we observed the expression of the stress protein (heat shock protein; inducible protein) from mouse tissues and evaluated the protective effects to hydroxyl radical in mouse brain cell culture. Cysteine, methionine or sodium sulfide was fed by oral administration of 1 ml/per 6hr/three times with 1 mM, 2mM or 3mM to mouse, respectively. After that, the stress proteins were extracted from mouse tissues and analyzed the features of expression. The stress proteins by sulfur containing compounds were showed different aspects in the kinds and concentrations of their compounds, and in the tissues of mouse. In the liver, the stress proteins were appeared at different time on the concentration of sulfur containing compounds and had less than 20 KDa as small molecules. In general, the molecular weights of stress protein in liver, the stress proteins were appeared at different time on the concentration of sulfur containing compounds and had less than 20 KDa as small molecules. In general, the molecular weights of stress protein in the spleen were evaluated from 32KDa to 50KDA, and the induced times were relatively late at high concentration of cysteine, early at low concentration of methionine or sodium sulfide. The stress proteins in mouse muscle were detected mostly between 24hr after treatment of sulfur containing compounds. Their molecular weights were 15~24KDa. In the antioxidative effects of sulfur containing compounds to hydroxyl radical, cell viabilities were measured by 63.2% at 10
, 65.5% at 50
, 68.6% at 100
, 78.3% at 150
, or 83.0% at 200
of cysteine, respectively. At addition of methionine, the cell viabilities were assessed as 58.1% at 10
, 62.8% at 50
, 75.7% at 100
, 78.6% at 150
, and 79.2% at 200
after 4hrs exposure with 20mU/ml glucose oxidase (GO) system, while the numbers of live cells to hydroxyl radicals in treatment of sodium sulfide were showed 48.6% at 10
, 54.8% at 100
, 51.8% at 150
, and 51.6% at 200
in the neuronal cells. In the inhibitory effects on the proliferation of tumor cells, percentages of dead cells of the CT-26 or HeLa cell were generally less than 30% even 48hr after addition of sulfur containing compounds. Conclusively, the results of these experiments indicate that stress protein by sulfur containing compounds can be used as physiological indicator for animal nutrition and for environment, and also that cysteine and methionine can play critical roles as an antioxidant.
2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin Induces Recruitment of Shc/Cbl/Grb2/Sos Conplex in Early Signaling Pathway of CYP1A1 Induction in the Primary Culture of Hepatocytes
Kim, Bok-Ryang ; Park, Rae-Kil ; Kim, Dong-Hyun ;
Toxicological Research, volume 15, issue 1, 1999, Pages 89~93
2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) is known to induce cytochrome p450 1A1 and to activate c-Src kinase and p21 Ras. This study examined the molecular interactions of adaptor proteins including Shc, Grb2, and Sos in rat primary hepatocytes and their relationship to the induction of CYP1A1 by TCDD. TCDD induced CYP1A1 level and EROD activity in a dose-dependent mode. Sos/Grb2 association isincreased by TCDDㅑㅜ a dose dependent mode. Tyrosine phosphorylated Shc, mainly p152, onloads to Grb2/Sos complex upon TCDD stimulation. The electrophoretic mobility shift of Sos is showed by TCDD. These results indicate that TCDD modulated the molecular interaction features of adaptor compoes proteins including Shc, Grb2, and Cnl in early signaling pathway of TCDD-mediated CYP 1A1 induction of rat primary hepatocyte.
The Effect of Dehydronifedipine on the Oxidation of Aflatoxin
by Cytochrome P450 3A4
Toxicological Research, volume 15, issue 1, 1999, Pages 95~101
Cytochrome P450 (CYP) 3A4 metabolizes aflatoxin B1 (AFB1) to AFB1-exo-8,9-epoxide (8,9-epoxidation) and aflatoxin Q1 (AFQ1; 3
-hydroxylation) simultaneously. We investigated whether each metabolite was formed via its own binding site of CAP3A4 active site. Kinetics of the formation of the two metabolites were sigmoidal and consistent with the kinetics of substrate activation. The HIll model predicted that two substrate binding wites are involved in the oxidationof AFB1 by CYP3A4. Dehydronifedipine, a metabolite of nifedipine generated by CYP3A4, inhibited the formation of AFQ1 without any inhibition in the formation of AFB1-exo-8,9-epoxidation. Dehydronifedipine was found to act as a reversible competitive inhibitor against 3
-hydroxylation of AFB1. Vmax and S0.5 of the 8,9-epoxidation were not changed in the presence of 0, 50, or 100
dehydronifedipine. S0.5 of 3
-hydroxylation was increased from 58
in the presence of 100
nifedipine whereas Vmax was not changed. These results suggest that there exist two independent binding sites in the active site of CAP3A4 . One binding site is responsible for AFB1-exo-8,9-epoxidation and the other is involved in 3
-hydroxylation of AFB1. Dehydronifedipine might selectively bind to the site which is responsible for the formation of AFQ1 in the active site of CYP3A4.
Acute Toxicity Study on Coptidis Rhizoma in Mice
Toxicological Research, volume 15, issue 1, 1999, Pages 103~107
In order to evaluate acute toxicity of Coptidis rhizoma, 6 week- and 13 week-old male ICR mice received Coptidis rhizoma extract (600~4,800 mg/kg body weight) orally, and toxicological responses were observed for consecutive 7 days. In the mice received relatively high concentration of Coptidis rhizoma(
1,200mg/kg), death occurred within 3 hrs after oral administration, and its ratio in 13 week-old mice was conspicuously higher than that in 6 week-old mice.
of Coptidis rhizoma were estimated to bi 2,575 mg/kg and 1,490 mg/kg body weight in 6 week and 13 week-old mice, respectively. Coptidis rhizoma-treated animals manifested a variety of abnormal clinical findings such as ptosis, crouching, lethargy, convulsion, bizarre behavior and truning sideway. These abnormalities also ranked highly in the 13 week-old mice compared to those in the 6 week-old mice. In addition to abnormal behaviors, Coptidis rhizoma(
1,200 mg/Kg) significantly elevated the urinary contents of bilirubin, urobilirubin, protein and glucose, and values in 13 week-old mice was higher than those in 6 week-old animals. No toxicological response was observed at concentration less than 600 mg/kg. Our results clearly demonstrate that susceptibility of mice to Coptidis rhizoma may be related with age, indicating that younger age mice is more resistant to the Coptidis rhizoma than the older, and toxicological mechanism of Coptidis rhizoma may be closely associated with its pharmacological mechanism.
Carnosine and Related Compounds Protect Against HOCI-Induced Damage of Biomolecules
Lee, Beom-Jun ; Park, Jae-Hak ; Lee, Yong-Soon ; Cho, Myung-Haing ;
Toxicological Research, volume 15, issue 1, 1999, Pages 109~115
The antiosidant activity of carnosine and related compounds such as anserine, homo-carnosine, histidine, and
-alanine which are found in most mammalian tissues, was investigated using hypochlorite (HOCl)-induced oxidant systems. Carnosine and related compounds were protective against HOCl-induced ascorbic acid oxidation, as determined by UV absorbance at 265nm. L-histidine was the most effective among them. The inhibitory effect of these compounds was strongly associated with a decrease in HOCl. It was also found that carnosine and related compounds significantly protected against the HOCl-mediated erythrocyte damage, as determined by hemoglobin release and gemolysis (p<0.05). Carnosine and anserine also inhibited of
-AP) by HOCl, thereby inactivating porcine elastase. The inhibitory effect of carnosine on inactivation of
-AP by HOCl depended on the concentration of carnosine and on the time preincubated with HOCl. Homocarnosine, histidine, and
-alanine did not inhibit the reaction. These results indicate that carnosine and related compounds can neutralize or scavenge HOCl. Thus, these compounds may play an important role in protecting against HOCl-mediated damage of biomolecules in vivo.