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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 14, Issue 4 - Dec 1998
Volume 14, Issue 3 - Sep 1998
Volume 14, Issue 2 - Jun 1998
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BRCA1 Protein Was Not Expressed in a Normal Human Breast Epithelial Cell Type With Stem Cell and Luminal Characteristics
Kang, Kyung-Sun ; Maki Saitoh ; Angelar Cruz ; Chan, Chia-Cheng ; Cho, Jae-Jin ;
Toxicological Research, volume 14, issue 2, 1998, Pages 123~127
BRCA1 is a tumor suppresser gene in familial cases of breast cancer. It has been controversial whether the subcellular localization of BRCA1 is located in nuclei or cytoplasm in normal human breast cells. We found that a p220 protein was expressed in Type II Normal human breast epithelial cells (NHBEC) but not in Type I NHBEC in Western blot analysis using the 17F8 (3A2) antibody. Immunostaining using the same antibody revealed positive staining in nuclei, cytoplasm and perinuclei of Type II cells and negative staining in Type I NHBEC. The p220 protein, however, was expressed in SV40 immortalized Type I NHBEC and tumorigenic cells derived from them after x-ray and neu oncogene treatment. The subcelluar localization was mostly cytoplasmic and punctate in the nuclei. The breast carcinoma cell lines, MCF-7 and T47D, also expressed the p220 protein. Using RT-PCR, we observed the expression of BRCA1 mRNA in both Type I and Type II NHBEC. This result indicated that there might be mechanisms involved in post-translational or translational regulation of BRCA1 gene. It is speculated that the absence of BRCA1 protein expression in Type I NHBEC might playa role in their susceptibility to neoplastic transformation.
A 4-Week Oral Toxicity Study of 2-Bromopropane in Sprague- Dawley Male Rats
Toxicological Research, volume 14, issue 2, 1998, Pages 129~141
Toxic effects of 2-bromopropane (2-BP) on the hematopoietic system and testis were investigated in male Srague-Dawley (SD) rats. 80 male SD rats, 5 weeks old, were treated with 2-BP in corn oil at levels of 0, 100, 330 and 1,000 mg/kg/day for 4 weeks orally. 10 animals from each group were maintained for additional 8 weeks following the treatment. In addition, 60 male SD rats were divided into 2 groups and administered 2-BP in corn oil at levels of 0 and 1,000 mg/kg/day orally and sacrificed after 1. 2 and 3 weeks of treatment. Clinical observation. body weight changes, food consumption, organ weight changes. hematology, serum chemistry and histopathology of the testis were performed in the study. No clinical sign and mortality were observed in the study. The body weights were significantly reduced with the treatment but gradually recovered. The relative organ weights of the testis and thymus significantly decreased in both of the groups treated with 1,000 mg/kg/day for 3 and 4 weeks. In the recovery groups, organ weights of the testis and epididymis were significantly reduced in both of the groups treated with 330 and 1,000 mg/kg/day. Platelets and reticulocytes were significantly reduced in both of the group treated with 1.000 mg/kg/day for 3 and 4 weeks. While red blood cells were de-creased but mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were increased in the recovery group. Significant increase of chloride was observed in all of the treatment groups except the recovery groups, and calcium was significantly increased in both of the groups treated with 1,000 mg/kg/ day for 3 and 4 weeks. On the other hand. there were significant decreases in alanine aminotransferase (ALT) and aspatate aminotransferase (AST) in most of groups treated with 1.000 mg/kg/day. In the testis. the spermatogonia in stages I-VI were mostly depleted and the spermatocytes in stages VII-VIII were de-generated or necrotized at week 1 after treatment of 2-BP. The degeneration of germ cells and the a-trophy of seminiferous tubules became more severe in time-dependent and dose-dependent manners. The damaged tubules showed regeneration in part. however. they did not appear to be completely recovered within 8 weeks of the recovery period. On the basis of the results. it is suggested that 2-BP would cause toxicities in hematopoiesis by possibly interfering the production of red blood cells and platelets and in spermatogenesis by the destruction oj spermatogonia in SD male rats.
Histopathological Observation and Flow Cytometry Analysis of Testicular Atrophy Induced by 2-Bromopropane On the Sprague-Dawley Rat
Toxicological Research, volume 14, issue 2, 1998, Pages 143~149
This study was carried out to evaluate the testicular toxicity of 2-bromopropane (2-BP), which recently caused occupational intoxication on the reproductive and hematopoietic system in Koreans, using light microscopy, immunohistochemistry and flow cytometry. 10 weeks old male Sprague-Dawley (SD) rats were treated with 0.5 g/㎏/day of 2-BP orally for 8 consecutive weeks. The testes of the rats were vascularly perfused with Karnovsky's solution or immersed in Bouin's solution, embedded in plastic and evaluated with light microscopy. And relative proportions of haploid, diploid, and tetra-ploid states of DNA ploidy in the testicular cell suspensions of the SD rats were examined by flow cytometry. 2-BP induced severe testicular atrophy, depletion and degeneration of spermatogonia, spermatocytes, and spermatids and mild hyperplasia of Leydig cells without significant morphological changes. The Leydig cell hyperplasia was confirmed by immunohistochemistry using proliferating cell nuclear antigen (PCNA). The immunopositive cells against PCNA were observed in the nuclei oj some interstitial cells. Relative proportions of haploid states of DNA ploidy decreased in the atrophic testicular cell suspensions comparing with those of the control. In conclusion, 2-BP induced testicular atrophy with Leydig cell hyperplasia as examined by histopathology, immunohistochemistry and DNA flow cytometry.
Nephrotoxicity of Acetaminophen and Gentamicin in Combination in Rats
Yoon, Sang-Don ; Lim, Chae-Woong ; Rim, Byung-Moo ;
Toxicological Research, volume 14, issue 2, 1998, Pages 151~156
Acetaminophen (APAP) and gentamicin are widely used for many patients, but little in-formation is available regarding the combined effects of APAP and gentamicin. This study was aimed to investigate the potent nephrotoxicity following combined-treatment with APAP and gentamicin. Serum biochemical parameters and histopathological changes in the kidney were observed in female SD rats after continuous daily treatment with either 600 mg/kg/day APAP, and/or 300 mg/kg/day gentamicin for 3 days, and compared with saline sham-treated control animals. APAP and gentamicin combination-treated rats exhibited inconsistent increasing tendency in blood urea nitrogen (BUN) by 96 hours after the last treatment, compared to control or the animals treated with each drug. The relative kidney weights were also increased. Histopathological findings of kidneys revealed that necrosis of proximal convoluted tubules were higher in rats treated with APAP and gentamicin combination than the rats treated with each drug alone. These results suggest that combination use of both drugs have more severe nephrotoxicity than treating each drug alone.
Aliphatic and Allyl Alcohol-Induced Liver Cell Toxicity and its Detoxification
Park, Su-Kyung ; Lee, Wan-Koo ; Park, Young-Hoon ; Moon, Jeon-Ok ;
Toxicological Research, volume 14, issue 2, 1998, Pages 157~161
The mechanism of active aldehyde-induced liver disease and the enzymatic basis of detoxification were investigated using normal rat liver cell, Ac2F. Aliphatic alcohols including l-decyl alcohol, l-nonanol, l-heptanol, l-hexanol, l-propanol and allyl alcohol exerted a dose- and time-de-pendent toxicity to Ac2F cells. The extent of their toxicities in buthionine sulfoximine (inhibitor of glutathione synthesis) pretreated cells was greater than in pargyline (inhibitor of aldehyde dehydrogenase, ALDH). On the other hand, the toxicity of these alcohols were not affected by 4-methylpyrazole (inhibitor of alcohol dehydrogenase, ADH). These results suggest that the contents of glutathione (GSH) seems to be very important in protecting the cells from toxicants such as aliphatic alcohols.
The Effect of Fluoride and Aluminum on Bone Turnover in Mouse Calvarial Culture
Ahn, Hye-Won ;
Toxicological Research, volume 14, issue 2, 1998, Pages 163~169
Fluoride (F), over a narrow concentration range, increases bone formation. Aluminum (Ai) too is biphasic in its action on bone, being mitogenic at very low levels and inhibitory at higher levels. Both F and Al are present in finished drinking water where the chemical interaction of these two agents is well characterized. F and AI, given individually, accumulate preferentially in bone. In addition. in vivo studies have shown that F causes the co-accumulation of Al in bone. Thus, it was necessary to determine the interactive effect of these two agents on bone mitogenesis. Calvaria were obtained from neonatal CD-1 mice and cultured with various concentrations of F (0.05~19 ppm) as NaF, Al (2 ppb~2 ppm) as
, or F and Al for 3 days at
on a rotating roller drum. Alkaline phosphatase activity in calvaria and
-glucuronidase activity in culture medium were determined as a measures of bone turnover. Alkaline phosphatase activity in calvaria was significantly increased by F (0.05~2 ppm) treatment and
-glucuronidase activity was slightly increased in the culture medium of calvaria treated with 0.3 ppm Al. The combination of 19 ppm F and 0.3 ppm Al increased alkaline phosphatase activity in calvaria, but did not affect
-glucuronidase activity, suggesting the interactive effect of fluoride and aluminum on bone turnover.
Effects of Natural Bioactive Substances on Hydroxyl Radical Mediated Cytotoxicity in Mouse Forebrain Cell Culture
Toxicological Research, volume 14, issue 2, 1998, Pages 171~176
The biological effects of the water extracts of Rhus Verniciflua Stokes (RVS) were evaluated by protection against hydroxyl radicals. Antioxidative activities were measured using both 1,1-diphenyl-2-picrylhydrazyl (DPPH) and thiocyanate method. Also we used the Glucose oxidase (GO) 20 mU/
hydroxyl radical generating system in mouse forebrain cell culture. Water was used for ex-traction from RVS as a solvent which has high polarity especially. In DPPH method, the antioxidative activities of the crude water extract were stronger than any other extracts of low polar-solvents. In the antioxidative effects of mouse forebrain culture using 20 mU/
GO, cell viabilities were evaluated 65.6%, 68.8% at 1
addition of crude water extracts (30 mg/
) respectively. 10
addition of crude water extracts had more than 86.1% cell viabilities, P<0.0l significantly, compared with the group treated with GO alone. In comparison with the antioxidative activities of several commercial antioxidants (ascorbic acid,
-tocopherol, catalase, serum), 273
addition of crude water extracts (300
) showed equivalent antioxidative effect to 25 uM ascorbic acid.
S-(N,N-Diallyldithiocarbamoyl)-N-acetylcysteine: Synthesis and Biochemical Properties Associated with Chemoprevention
Toxicological Research, volume 14, issue 2, 1998, Pages 177~181
Dithiocarbamate and mixed disulfide containing allyl functions were designed and synthesized as putative chemopreventive agents, i.e. N,N-diallyldithiocarbamate (DATC) and S-(N,N-diallyldithiocarbamoyl)-N-acetylcysteine (AC-DATC). DATC and AC-DATC were administered and the activities of cytosolic glutathione S-transferase (GST), glutathione reductase (GR) and microsomal N-nitrosodiethylamine (NDEA) deethylase were assayed in order to test the effects of these organosulfur com-pounds on the detoxification and metabolic activation system of NDEA. The amounts of hepatic glutathione (GSH and GSSG) was also determined. The administration of DATC to rats led to an increase in the activity of GR and to an inhibition of CYP2E1-mediated NDEA deethylation. AC-DATC induced the activity of GR and GST, increased the hepatic GSH content and inhibited the rate of NDEA deethylation. The level of GSSG was decreased as a consequence of the increased activity of GR. These effects may contribute to possible antimutagenic and anticarcinogenic action of the dithiocarbamates investigated.
Genernal Pharmacological and Acute/Subacute Toxicity Test of House Dust Mite Extract in Mice, Rats, and Guinea pigs
Toxicological Research, volume 14, issue 2, 1998, Pages 183~191
It has been reported that 50~70% of child asthma, bronchial asthma in adult, and allergic rhinitis are caused by house dust mite. The antigen extracted from house dust mite has been used for effective treatment against allergic diseases and for clinical test. This house dust mite antigen has been entirely imported from abroad. However, the composition and content of all the antigen imported vary from a brand to other brand. Thus, we need to standardize the composition and content of the antigen by developing it domestically. We proceeded pre-clinically general pharmacological test and toxicological test that are required for the eventual human use by utilizing the house dust mite cultured in Korea. In order to obtain information on general pharmacological tests such as its toxic signs in tissues or organs which are mainly affected, we examined the effect of house dust mite on the tensions of the isolated tissues and heart rates of cardiac muscle by recording with force displacement transducer of polygragh (Glass Model 7). We determined lethality of antigen extracted from house dust mite in mice and guinea pigs. We examined acute and subacute toxicity by administrating house dust mite extract of 500, 100, 20 times of the expected clinical dose. In male and female mice and guinea pigs, given a sigle intraperitoneal dose of antigen,
values were over 5.0
/kg, respectively. In animals administrated with house dust mite, there were no significant change of clinical symptom, body weight, food consumption, water consumption, eye examinations, urinalysis, blood biochemistry, and histopathological examinations in any animals tested. We found no toxic effect of this house dust mite. These results show that the house dust mite cultured by us could be used in the development of medicine against allergic diseases caused by the antigen of house dust mite.
Male Reproductive Toxicity of DA-125, a New Anthracycline Anticancer Agent, in Rats
Toxicological Research, volume 14, issue 2, 1998, Pages 193~203
The toxicity of DA-125. a new anthracycline anticancer agent, on the male reproductive system was studied in Sprague-Dawley rats. Forty male rats were rando
y assigned to Jour groups with ten rats in each group and given single intraveneous doses of DA-125 at dose levels of 0. 12.5. 25. and 50 mg/kg body weight. On day 56 after treatment the animals were allowed to mate. and their male reproductive Junctions and organs were examined in detail. Copulated females were sacrificed on day 20 of gestation for examination of embryo-fetal development. One out of ten rats in the 50 mg/kg group died on day 12 after treatment. Clinical signs such as emaciation. sedation, anorexia. swelling. dark material around eye. alopecia. and diarrhea were observed in the 25 and/or 50 mg/kg groups. Reduction in the body weight gain. decrease in the absolute weights of testes. epididymis and seminal vesicles. and/or decrease in the number of testicular sperm heads were also found. Although histopathological changes such as atrophy of seminiferous tubules. loss or decrease of spermatogenic cells. exfoliation of spermatogenic cells. vacuolization of Sertoli cells. decrease of sperm. and/or increase of necrotic spermatogenic cells in epididymal ducts were observed. no adverse effects on the motility and morphology of epididymal sperm. copulation index. fertility index. and embryo-fetal development were detected in the 25 and 50 mg/kg groups. There were no evidences of male reproductive toxicity in the 12.5 mg/kg group. These results show that single intravenouse doses of DA-125 produce significant dose-related testicular atrophy. histopathological changes. and oligozoospermia in rats and
for DA-125 appears to be 50 mg/kg body weight.
Evaluation of Immunotoxicities of New Skin Decontamination Kit(SDK)
Toxicological Research, volume 14, issue 2, 1998, Pages 205~209
To evaluate immunotoxicity of skin decontamination kit(SDK) newly-developed in Agency for Defense Development(ADD), delayed contact hypersensitivity (maximization) test and passive cutaneous anaphylaxis(PCA) test of SDK were performed and the results were compared with those of M 291. In maximization test, sensitization reaction was induced by id injection (2.5 mg / 0.1
/ guinea pig or 2.5 mg+CFA/0.1
/guinea pig) and topical application (2.5 mg/
/guinea pig) with SDK or M291 at an interval of 1 week, and 2 weeks later, challenged by topical application with 25 mg/
/guinea pig. SDK and M291 did not induce any reactions, showing 0 point of sensitization score and 0% of sensitization rate. In conclusion, it is suggested that SDK and M291 do not induce delayed contact hypersensitivity. In PCA test, rats were administered id with mouse anti-SDK serum and challenged iv with a mixture of antigen SDK and Evan's blue. SDK did not induce blue spots at the injection sites of both high (2.5 mg/mouse) and low (1.25 mg/mouse) dose-induced antisera. In contrast, BSA, positive control produced spots larger than 5 mm in diameter at the injection sites of BSA-induced antiserum up to
dilution. In conclusion, it is suggested that SDK do not induce IgE production and is not a PCA-reaction inducer.
Mutagenecity Test of SDK
Toxicological Research, volume 14, issue 2, 1998, Pages 211~216
In order to evaluate the mutagenic potential of SDK(skin decontamination kit) produced by Agency for Defense Development(ADD), were performed Salmonella typhimurium reversion assay, chromosomal aberration test on chinese hamster ovarian cells and in vivo micronucleus assay using mouse bone marrow cells according to the established regulation of Korean Food and Drug Administration. In the reverse mutation test using Salmonella typhimurium TA98, TA100, TA1535 and TA1537 did not in-crease the number of revertant at any of the concentration tested in this study. SDK did not increase the number of cells having structural or numerical chromosome aberration in cytogenetic test. In mouse micronucleus test, no significant increase in the occurrence oj micro nucleated polychromatic erythrocytes were observed in ICR male mice intraperitoneally administered with SDK. These results indicate that SDK has no mutagenic effects under these experimental conditions.
Four-Week Topical Toxicity Studies of SDK in Beagle Dogs and Sprague-Dawley Rats
Toxicological Research, volume 14, issue 2, 1998, Pages 217~226
SDK (skin decontamination kit) is new skin decontaminant which is developed by ADD (Agency for defence development). In this study, four-week toxicity of SDK was investigated using beagle dogs and Sprague-Dawley rats. The beagle dogs and Sprague-Dawley rats were dressed topically seven days per week for 28 days, with dosage of 0, 0.25, 0.8 and 1 g/kg/day. respectively. Animals treated with SDK did not cause any death and show any clinical signs. They did not show any significant changes of body weight, feed uptake and water consumption. They were not significantly different from the control group in urinalysis, ocular examination and histopathological examination. In hematological and serum biochemical assay, there were no-dose-defendent changes. Therefore, SDK was not indicated to have any toxic effect in the beagle dogs and Sprague-Dawley rats when it was dressed topically below the dosage 1 g/kg/day for four weeks.
Acute Toxicity Test of KH-502 (Flupyrazofos) in Rats and Mice
Toxicological Research, volume 14, issue 2, 1998, Pages 227~235
KH-502 (Flupyrazofos), a new organophosphorus insecticide synthesized by Korea Re-search Institute of Chemical Technology, was found to be effective against diamond-back moth(Plutella xylostella). This study was carried out to determine the acute toxicity of KH-502 in Sprague-Dawley rats and ICR mice. The test article was orally or dermally administered to the animals. Death, tremors, salivation, lacrimation, abnormal gait and corneal opacity were observed. Decrease in body weight gain was observed in all treatment groups. At necropsy, dark red coloration of lung, enlargement of adrenal glands and atrophy of spleen were observed. The oral
value was 372 mg/kg in male rats, 605 mg/kg in female rats, 186 mg/kg in male mice, and 115 mg/kg in female mice. And the dermal
was 4086 mg/kg in male and 3881 mg/kg in female rats.
Acute and Subacute Toxicity of New Woohwangchungsimwon in Rats
Toxicological Research, volume 14, issue 2, 1998, Pages 237~248
The acute and subacute toxicity of New Woohwangchungsimwon(NWCH) which was used l-muscone as substitutive material of musk were investigated in S.D. rats. In intraperitoneal acute toxicity test. rats(Sprague-Dawley, SPF) were injected intraperitoneally with dosages of 0, 540, 750, 1,070, 1.500 and 3,000 mg/kg. Body weights were significantly decreased at 540 mg/kg dose group in both sexes and abnormal autopsy findings were founded in both sexes at all treated groups. Intraperitoneal
of NWCH was 812.3 mg/kg in male and 872.3 mg/kg in female rats. In the subacute toxicity study, NWCH was administrated orally to both sexes of rats for 4 weeks as several doses(0, 320, 800 and 2, 000 mg/kg). There were neither dead animals nor significant changes of body weights during the experimental period. In addition, no differences were found between control and treated groups in clinical signs, urinalysis, hematology, serum biochemical analysis, and other findings. Above data strongly suggest that no observed adverse effect level of NWCH might be over 2,000 mg/kg/day in this study.
Acute and Subacute Toxicity of New Woohwangchungsimwon in Beagle Dogs
Toxicological Research, volume 14, issue 2, 1998, Pages 249~260
Single and 4 weeks oral administration of New Woohwangchungsimwon (NWCH) which was used l-muscone as substitutive material of musk, to beagle dogs of both sexes were performed to investigate both acute and subacute toxicity. Beagle dogs(3 males and 3 females) in acute experiments were administered orally with single dose of 2,000 mg/kg and groups of 9 male and 9 female beagle dogs in subacute experiments were given daily different dosage of NWCH, 160 mg/kg/day (low dosage group), 400 mg/kg/day (middle dosage group), 1,000 mg/kg/day (high dosage group) once a day for 4 weeks by oral route according to the Established Regulation of Korea Food and Drug Administration (1996. 4. 16).
/ value for beagle dogs was more than 2,000 mg/kg per oral for both male and fe-males. In animals administered with NWCH, there were neither dead animals nor significant changes of body weights. In addition, no differences were found between control and treated groups in clinical sign, urinalysis, eye examination, hematology, serum chemistry, organ weight and other fingings. No histological lesions were observed in both control and treatment groups. Above data strongly suggset that NWCH in beagle dogs is considered to be safe.
Acute and Subacute Toxicity Studies of New Wonbangwoohwangchungsimwon in Rats
Toxicological Research, volume 14, issue 2, 1998, Pages 261~271
The acute and subacute toxicity of New Wonbangwoohwangchungsimwon (NSCH) which was used l-muscone as substitutive material of musk were investigated in S.D. rats. In intraperitoneal acute toxicity test, rats were injected intraperitoneally with five dosages of 0, 500, 710, 1,000, 1,410 and 2,000 mg/kg. Body weights were significantly decreased at 500 and 710 mg/kg dose group in male and abnormal autopsy findings were founded in both sexes at all dose. Intraperitoneal
of NSCH was 1,088.3 mg/kg in male and 1159.3 mg/kg in female rats. In the subacute toxicity study, NSCH was administrated orally to both sexes of rats for 4 weeks as several doses(0, 320, 800, and 2,000 mg/kg). There were neither dead animals nor significant changes of body weights during the experimental period. In addition, no differences were found between control and treated groups in clinical signs, urinalysis, hematology, serum biochemical analysis, and other findings. Above data strongly suggest that no observed adverse effect level of NSCH might be over 2,000 mg/kg/day in this study.
Acute and Subacute Toxicity Studies of New Won-bangwoohwangchungsimwon in Beagle Dogs
Toxicological Research, volume 14, issue 2, 1998, Pages 273~283
Single and 4 weeks oral administration of New wonbangwoohwangchungsimwon (NSCH) which was used l-muscone as substitutive material qf musk, to beagle dogs of both sexes were per-formed to investigate both acute and subacute toxicity. Beagle dogs (3 males and 3 females) in acute experiments were administered orally with single dose of 2,000 mg/kg and groups of 9 male and 9 female beagle dogs in subacute experiments were given daily different dosage of NSCH, 160 mg/kg/day (low dosage group), 400 mg/kg/day (middle dosage group), 1,000 mg/kg/day (high dosage group) once a day for 4 weeks by oral route according to the Established Regulation of Korea Food and Drug Ad-ministration (l996. 4. 16).
value for beagle dogs was more than 2,000 mg/kg per oral for both male and females. In animals administered with NSCH, there were neither dead animals nor significant changes of body weights. In addition, no differences were found between control and treated groups in clinical sign, urinalysis, eye examination, hematology, serum chemistry, organ weight and other fingings. No histological lesions were observed in both control and treatment groups. Above data strongly suggset that NSCH in beagle dogs is considered to be safe.