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The Korean Society of Toxicology
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Volume 18, Issue 4 - Dec 2002
Volume 18, Issue 3 - Sep 2002
Volume 18, Issue 2 - Jun 2002
Volume 18, Issue 1 - Mar 2002
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Toxicokinetic Models and Data Interpretation
Toxicological Research, volume 18, issue 4, 2002, Pages 311~324
Toxicokinetic studies are intended to provide critical evaluation of drug disposition at toxico-logical doses and help understand the relationship between blood or tissue levels and the time course of toxic events. Relatively high dose levels wed in toxicokinetics, compared to pharmacokinetics, complicates absorption, protein binding, metabolism and elimination processes. In this mini review, frequently wed toxicokinetic models such as linear compartment models, physiological models, and nonlinear kinetic mod-ec are introduced. In addition, optimization of toxicokinetic studies, their role in the drug development process, and prediction oj human toxicokinetics based on animal data by interspecies scaling are briefly discussed.
Influences of CYP2E1 Gene Polymorphism on the Metabolism of Benzene
Toxicological Research, volume 18, issue 4, 2002, Pages 325~330
In this study, the biochemical role of genetic polymorphism in modulating urinary excretion of benzene metabolite as phenol level has been investigated in 90 workers exposed to benzene in the petroleum refinery plant of Korea. The mean concentration of volatile benzene in the refinery environment was 0.042 mg/㎥ (SD, 0.069) and that of urinary phenol was 7.42 mg/g creatinine (SD, 11.3). The frequencies of CYP2E1 genotypes, namely CYP2E1
were 2.2% (2 subjects), 6.7% (G subjects) and 91.1% (85 subjects), respectively, and allele frequencies for CYP2E1
were 0.06 and 0.94. The airborne benzene concentration was significantly related to the concentration of phenol in urine (r = 0.640, p < 0.01). The urinary phenol level was significantly correlated with CYP2E1
(r = 0.590, p < 0.05). The various biological (i.e. age and liver function parameters) or lifestyle factors (i.e. medication, smoking, alcohol and coffee intake), also taken into account as potential confounders, did not influence the correlation found. These results suggested that CYP2E1 genotypes might play an important role in the metabolism of benzene.
Mechanism of Phenoxy Compounds as an Endocrine Disrupter
Toxicological Research, volume 18, issue 4, 2002, Pages 331~339
Phenoxy compounds, 2,4-Dichlorophenol acetoxy acid (2,4-D) and 2,4-dichlorophenol (DCP), are widely used as a hormonal herbicide and intermediate for pesticide manufacturing, respectively. In order to assess the potential of these compounds as endocrine disruptors, we studied the androgenicity of them wing in vivo and in vitro androgenicity assay system. Administration of 2,4-D (50 mg/kg/day, p.o.) or DCP (100 mg/kg/day, p.o.) to rats caused an increase in the tissue weight of ventral prostate, Cowpers gland and glands penis. These increase of androgen-dependent tissues were additively potentiated when rats were simultaneously treated with low dose of testosterone (1 g/kg, s.c.). 2,4-D increased about 350% of the luciferase activity in the PC cells transiently cotransfected phAR and pMMTV-Luc at concentration of
M. In 2,4-D or DCP-treated castrated rats, testosterone 6
-hydroxylase activity was not significantly modulated even when rats were co-treated with testosterone. In vitro incubation of 2,4-D and DCP with microsomes at 50
M inhibited testosterone 6
-hydroxylase activity about 27% and 66% in rat liver microsomes, about 44% and 54% in human liver microsomes and about 50% and 45% in recombinant CYP3A4 system, respectively. The amounts of total testosterone metabolites were reduced about 33% and 75% in rat liver microsomes, 69% and 73% in human liver microsomes and 54% and 64% in recombinant CYP3A4 by 2,4-D or DCP, respectively. Therefore, the additive androgenic effect of 2,4-D or DCP by the co-administration of the low dose of testosterone may be due to the increased plasma level of testosterone by inhibiting the cytochrome P450-mediated metabolism of testosterone. These results collectively suggested that 2,4-D and DCP may act as androgenic endocrine disrupter by binding to the androgen receptor as well as by inhibiting the metabolism of testosterone.
Association Study between the Genetic Variations of the Apo AI-CIII-AIV Gene Cluster and Hypertension among Koreans
Kang, Byung-Yong ; Kang, Chin-Yang ; Ki, Tae-Kim ; Bae, Joon-Seol ; Oh, Sang-Duk ; Kim, Jae-Hyun ; Lee, Kang-Oh ;
Toxicological Research, volume 18, issue 4, 2002, Pages 341~347
Hypertension is a multifactorial disorder in which the genetic and environmental factors are involved. In a view of the effects for hypertension as a risk factor for hypertension, we investigated the genotype and allele frequencies in the four RFLPs of the apo AI-CIII-AIV gene cluster (G to A mutation at position -75 in the apo AI promoter SstI RFLP in the ape CIII gene and HincII and HinfI RFLPs in the apo AIV gene) in the Korean patients with hypertension and normal controls. The AA genotype frequency of the G to A promoter polymorphism in hypertensives was significantly higher than that of normotensives (P < 0.05). None of the other polymorphisms showed a difference in genotype frequency between two groups. Therefore, our result suggest that the G to A promoter polymorphism of the ape AI gene may be useful as genetic marker in the ethiology of hypertension.
Genotoxicity Studies of DA-6034, a New Flavonoid Derivative
Toxicological Research, volume 18, issue 4, 2002, Pages 349~354
Inflammatory bowel disease (IBD) is a multifactorial disorder with unknown etiology and pathogenesis. Eupatilin, a kind of flavonoids, has been known to be effective for chronic diarrhea in Korea. In this study, we have investigated the genotoxicity of DA-6034, a new synthetic derivative of Eupatilin, wing in vitro and in viuo system such as Ames reverse mutation test, chromosomal aberration test and micronucleus test. in Ames reverse mutation test, DA-6034 treatment at the dose range up to 5,000
/ plate did not induced mutagenicity in Salmonella typhimurium TA98, TA100, TA102, TA1535, TA1537 with and without metabolic activation. Any significant aberration wasn't observed in chinese hamster lung(CHL) fibroblast cells treated with DA-6034 at the concentration of 5, 2.5, 1.25 mg/ml both in the absence and presence of metabolic activation system. In mouse micronucleus test, no significant increase in the occurrence of micronucleated polychromatic erythrocytes was observed in ICR male mice orally administered with DA-6034 of the doses of 2.0, 1.0, 0.5 g/kg. These results indicate that DA-6034 has no mutagenic potential under the condition in this study.
Intracellular Calcium Concentration in the Glutamate-induced Cytotoxicity in PCl2 Cell
Toxicological Research, volume 18, issue 4, 2002, Pages 355~362
Pathophysiological elevation of intracellular calcium concentration (
) in the neuron has been considered as an important responsible factor in the neuronal cell damages. However the mechanism of increase of
and the relationship between
level and cytotocixity have not been fully demonstrated. In the present study, real-time alteration of
and cellular response (cell damages) in the pheochromocytoma cells (PC12) stimulated by glutamate were investigated. Glutamate dose dependently decreased cell viability determined propidium iodide fluorescence method and morphology change. Conversely related with cell damages, glutamate dose dependently increased the level of［Ca
. To investigate the mechanism of glutamate-induced increase of
, was first measured in the cell cultured in calcium free media and in the presence of dantrolene, an inhibitor of calcium release from ryanodine receptor located in endoplasmic reticulum (ER). Similar to the increase
in the calcium-containing media, glutamate dose dependently increased
in the cell cultured in free calcium media. However pretreatment (2 hr) with 20~50
dantrolene substantial lowered glutamate-induced increase of
, suggesting that release of calcium from ER may be major sourse of increase of
in PC12 cells. Dantrolene-induced inhibition of
resulted in recovery of cytotoxicity by glutamate. Relevance of N-methy-D-aspartate (NMDA) receptor, a type of glutamte receptor on glutamate-induced incense of
was also determined in the cells pretreated (2 hr) with NMDA receptor antagonist MK-80l. Glutamate-induced increase of
was reduced by MK-801 dose dependently. Furthermore, glutamate-induced cytotoxicity was also prevented by MK-80l. These results demonstrate that glutamte increase
dose dependently and thereby cause cytotoxicity. The increase of
may release from ER, especially through ryanodine receptor and/or through NMDA receptor Alteration of calcium homeostasis through disturbance of ER system and/or calcium influx through NMDA receptor could contribute glutamate-induced cell damages.s.
Inhibition of IgM Secretion in Murine B Cell Lymphoma by Hydrogen Peroxide
Jang, Eun-Jung ; Jo, Sung-Kee ; Yoo, Byung-Sun ;
Toxicological Research, volume 18, issue 4, 2002, Pages 363~367
Reactive of gen species (ROS) contribute to several cellular function and are involved in the regulation of signal transduction, gene expression, and proliferation. In the present study, we investigated the effect of
treatment on IgM secretion in LPS-stimulated murine B Iymphoma, CH12.LX. Cells were treated directly With
and stimulated with LPS.
treatment during 72 h time period inhibited IgM secretion in LPS-stimulated CH12.LX cells in a dose- and time-dependent manners. After treatment with 50
during 72 h time period, the level of IgM in LPS-stimulated CH12.LX cells was markedly decreased, whereas cell viability was not significantly changed. Addition of
concomitantly with LPS, or 12 h post-LPS stimulation, produced a significant inhibition of IgM secretion, Whereas inhibitory effect of
on IgM secretion was not observed when added 24 h after LPS stimulation. These findings suggest that
can inhibit the secretion of IgM in LPS-stimulated CH15.LX cells, and may alter the events necessary for terminal B cell differentiation.
Computerized Image Analysis of Micronucleated Reticulocytes in Mouse Bone Marrow
Toxicological Research, volume 18, issue 4, 2002, Pages 369~374
The present study was performed to validate an automated image analysis system (Loats Automated Micronucleus Scoring System) for the mouse bone marrow micronucleus assay, comparing with conventional microscopic scoring. Two studies were conducted to provide slides for a comparison of micro-nucleated polychromatic erythrocytes (MNPCEs) values collected manually to those collected by the auto-mated system. Test article A was used as an example of a compound negative for the induction of micronuclei and test article B was wed as a micronucleus-inducing agent to elicit a positive response. Cyclophosphamide was included to provide an positive control in two studies. Bone marrow samples were collected 24 h after administration of test article A and B in male ICR mice. The cells were fixed with absolute methanol and stained with May-Grunwald and Giemsa. The number of MNPCEs was determined by the analysis of 1000 total PCEs per bone marrow sample. In addition to micronucleus scoring, an index of bone marrow toxicity based on PCE ratio (% of PCEs to total erythrocytes) was determined for each sample. The automated and manual scoring was similar when the MNPCEs incidence induced by each test article was less than 10. However manual scoring was able to effectively enumerate micronucleated PCEs in mouse bone marrow when MNPCEs incidence was more than 10, such as cyclophosphamide treatment. Conversely, PCE ratio was superior in computer-assisted image analysis. Taken together, it is suggested that improvement of the automated image analysis may be necessary to render the automatic scoring as sensitive as manual scoring for routine counting of micronuclei, especially because it is superior in objectivity and high throughput scoring.
Four-Week Repeated-Dose Toxicity Studies of Hyrubicin ID6105, a Novel Anthracycline Anticancer Agent, in Rats
Toxicological Research, volume 18, issue 4, 2002, Pages 375~384
Repeated-dose toxicity of hyrubicin ID6105, a novel anthrarycline anticancer agent, was investigated in Sprague-Dawley rats. ID6105 was injected intravenously to rats at dose levels of 0.04, 0.2 or 1.0 mg/kg/day for 4 week. As a result, there were no dose-related mortality and specific clinical signs of all animals treated with the drug. However body weight gain of both male and female rats treated with a high dose (l.0 mg/kg/day) of ID6105 significantly decreased compared to control. Interestingly, the numbers of RBC and platelets, and concentration of hemoglobin remarkably increased, while protein synthesis was suppressed, which may be related to the atrophy of spleen, thymus and liver. Moreover there were severe lymphocytic depletion in spleen and thymus as well as decrease in the number of hematopoietic cells in bone marrow. Also, degeneration of cardiac muscles and testicular germinal epithelia were observed. Taken together, it is suggested that Long-term administration of ID6105 at high doses over 0.2 mg/kg/day might cause hematopoietic and male reproductive system injuries, in addition to hepatic dysfunction.
Genotoxicity Tests on Hyrubicin ID6105, a Novel Anthracycline Anticancer Agent
Toxicological Research, volume 18, issue 4, 2002, Pages 385~391
The genotoxic potential of Hyrubicin lD6105, a novel anthracycline anticancer agent, was examined on bacterial mutagenicity, mammalian cell chromosome aberration and mouse micronucleus tests. In mutagenicity (Ames') test, Salmonella typhimurium strain TA98, TA100, TA1535 and TA1537, and Escherichia coli WP2uvrA- were treated with ID6105 at doses of 312.5, 625, 1,250, 2,500 and 5,000
/ plate with or without a metabolic activation system (S9 mix). Interestingly, ID6105 significantly enhanced the number of revertant colonies of TA98 strain at all dose levels used, in the presence or absence of S9 mix, without affecting other strains of S. typhimurium and E. coli. In chromosome aberration test using cultured chinese hamster lung fibroblasts, ID6105 (1.25, 2.5 and 5
/ml) did not increase the number of aberrant cells, compared with vehicle control. in the presence or absence of S9 mix. In addition, ID6105 treatment (2.5, 5 and 10 mg/kg) did not induce micronucleated polychromatic erythrocytes in mice. Taken together, it is suggested that ID6105 might not affect chromosome integrity in mammalian system in vitro and in vivo, although it may induce frame shift mutation of specific bacterial strain such os S. typhimurium TA98.
The Evaluation of Estrogenic/Antiandrogenic Activity of Puerariae Radix in Immature Rats Using Uterotrophic Assay and Hershberger Assay
Toxicological Research, volume 18, issue 4, 2002, Pages 393~396
This study was carried out to evaluate the ostrogenic/antiandrogenic activity of Puerariae Radix in Sprague-Dawley rats. It has known that diverse phytoestrogen were included in some Puerariae Radix, especially in Pueraria mirifica. The Uterotrophic assay and Hershberger assay were performed to evaluate the ostogenic/antiandrogenic activity of various Puerariae Radix (Pueraria thunbergiana, Pueraria mirifica and Butea superba). In Uterotrophic assay, the extracts of Puerariae Radix were administered subcutaneously to immature female SD rats from 19 to 21 days of age. The wet uterus and vaginal weighs significantly increased in the group only treated with extracts of Pueraria mirifica. But, in Hersh-berger assay, all extracts of Puerariae Radix did not show any effects in the castrated rats. These results suggest that Pueraria mirifica has not undrogenic/antiandrogenic effect but potent estrogenic effect. It is possible that components of Pueraria mirifica may act as endocrine disruptor in human body.
Acute Oral Toxicity of G. bimaculatus in Rats
Toxicological Research, volume 18, issue 4, 2002, Pages 397~400
This study was carried out to investigate the acute toxicity of G. bimaculatus in Sprague-Dawley rats. G. bimaculatus was administered orally at doses of 8, 40, 200, 1000 and 5000 mg/kg. in this study, number of deaths, clinical sign, body weights, and pathological examination were investigated for 14 days after administration of G. bimaculatus. The results indicate that G. bimaculatus did not show any toxic effect in rats and oral
value was over 5000 mg/kg in Sprague-Dawley rats.
Developmental Immunotoxicity in SD Rat Pups Exposed by Di(n-butyl) Phthalate through Pre and Postnatal
Toxicological Research, volume 18, issue 4, 2002, Pages 401~409
Phthalate esters have possible effects on the endocrine system. Di-n-butyl phthalate (DBP) is one of the most commonly wed phthalic acid esters (PAEs). It is extensively wed as a plasticizer in elastomers, as a solvent for printing inks and resins, and as a textile lubricating agent. It is also present in the formulations of various cosmetic products. DBP has been identified as a reproductive toxicant in several animal species and also know as a endocrine disruptor. The objective of this study was to investigate the effect of DBP on developmental immune Junction wing rat pups as experimental animals. Timed-bred pregnant SD rats were orally dosed with 0, 250, 500, or 750 mg DBP/kg body weight once a day from gestational day (GD) 5 to 18 and postpartum day (PD) 3 to 18. On PD22, the dams and their pups were euthanized and examined for alteration in parameters associated to immune function. The results showed no significant changes in body weight, thymus weight, thymus and spleen cellularities, the polyclonal activation respones of splenocyte with ConA and LPS, and also the distribution of arterial blood cells and thymocyto subsets in both rat dam and pups. However DBP exposure on rat dam resulted in increases of liver weights of dam and their pups except 750 mg DBP/kg, and body and spleen weights in pups except 750 mg DBP/kg. On the other hands, distribution rates of CD8+ T cells at 500 mg DBP/kg and B cells at 750 mg DBP/kg among splenocyte subsets were significantly increased in rat pups, unlike dams. Reasons of these distribution alterations of CD8+ T cells and B cells in rat pups are under study.
Antisense bcl-2 Treatment in Human Lung Cancer Cell Lines
Toxicological Research, volume 18, issue 4, 2002, Pages 411~416
Apoptosis, or programmed cell death, is a genetically regulated pathway that is altered in many cancers. Overexpression of bcl-2 leads to resistance to apoptosis and promotes tumorigenesis. To determine the effect of bcl-2 antisense treatment in human lung cancer cell lines, a 20 mer full phosphorothioate oligonucleotide (ODN) targeted at the coding region of the bcl-2 mRNA was synthesized. Western blot analyses were used to examine bcl-2 protein level in five human non-small cell lung cancer (NSCLC) cell lines (NCI-H226, SK-MES-1 NCI-H358, NCI-H522 and NCI-Hl 299) and four human small cell lung cancer (SCLC) cell lines (NCI-H69, NCI-H4l7, HCC-2108 and SW2). Three out of five NSCLC (NCI-H226, SK-MES-1 and NCI-Hl 299) and all of SCLC cell lines expressed Bcl-2 protein. Treatment of these cell with antisense ODN for 48 hours reduced their viability and Bcl-2 protein level. As a conclusion, bcl-2 antisense treatment appears reduction of the Bcl-2 protein levels and cytotoxic effect including apoptosis in human lung cancer cell lines.