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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 19, Issue 4 - Dec 2003
Volume 19, Issue 3 - Sep 2003
Volume 19, Issue 2 - Jun 2003
Volume 19, Issue 1 - Mar 2003
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Replicative Senescence in Cellular Aging and Oxidative Stress
Toxicological Research, volume 19, issue 3, 2003, Pages 161~172
Explanted mammalian cells perform a limited number of cell division in vitro and than are arrested in a state known as replicative senescence. Such cells are irreversibly blocked, mostly in the G1 phase of cell cycle, and are no longer sensitive to growth factor stimulation. Thus replicative senescence is defined as a permanent and irreversible loss of replicative potential of cells. For this characteristic, replicative senescence seems to evolve to protect mammalian organism from cancer. However, senescence also contributes to aging. It seems to decrease with age of the cell donor and, as a form of cell senescence, is thought to underlie the aging process. Extensive evidence supports the idea that progressive telomere loss contributes to the phenomenon of cell senescence. Telomeres are repetitive structures of the sequence (TTAGGG)n at the ends of linear chromosomes. It has been shown that the average length of telomere repeats in human somatic cells decreases by 30∼200 bp with each cell division. It is generally believed that when telomeres reach a critical length, a signal is activated to initiate the senescent program. This has given rise to the hypothesis that telomeres act as mitotic clocks to regulate lifespan. One proposes that cumulative oxidative stress, mainly reactive oxygen species generated from mitochondria, may mainly cause telomere shortening, accelerating aging. Here, the biological importance and mechanism of replicative senescence were briefly reviewed. Also it was summarized that how oxidative stress affects replicative senescence and telomere shortening.
Toxicity Study of Red Ginseng Acidic Polysaccharide (RGAP) : Single and 2-week Repeated Oral Dose Toxicity Study in Rats
Park, Jong-Dae ; Song, Yong-Bum ; Kwak, Yi-Seong ; Kim, Jong-Choon ; Im, Doo-Hyun ; Junghee Han ;
Toxicological Research, volume 19, issue 3, 2003, Pages 173~180
The present study was conducted to investigate the single and 2-week repeated dose toxicity of red ginseng acidic polysaccharide (RGAP) in Sprague-Dawley rats. The test article was administered orally to rats at dose levels of 0, and 2000 mg/kg/day for single dose toxicity study and at dose levels of 0, 250, 500, and 1000 mg/kg/day for repeated dose toxicity study. In both studies, there were no treatment-related effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights of all animals treated RGAP. Based on these results, it was concluded that the 2-week repeated oral dose of RGAP may have no toxic effect in rats at a dose level of 1000 mg/kg/day. In the condition of this study, the no-observed-adverse-effect level (NOAEL) was considered to be 1000 mg/kg/day for both sexes.
Effects of Butylated Hydroxyanisole on Glutathione S-Transferases Activity and Cyclophosphamide-Induced Teratogenicity in Rats
Toxicological Research, volume 19, issue 3, 2003, Pages 181~187
Effects of repeated treatment with butylated hydroxyanisole (BHA) on the induction of glutathione S-transferases (GSTs) and teratogenicity of cyclophosphamide were investigated in rats. Pregnant rats were orally treated with BHA (50 mg/kg) for 7 days, from days 6 to 12 of gestation, and intraperitoneally challenged with cyclophosphamide (15 mg/kg) 2 hr after the final treatment. On day 20 of gestation, the maternal and fetal abnormalities were examined. Separately, a part of rats was sacrificed for the assay of hepatic and placental GSTs activities on day 12 of gestation following 7-day treatment with BHA. Cyclophosphamide, administered on day 12 of gestation, induced 43.2% of fetal death and resorption, and 100% of malformations in live fetuses, in contrast to low fetal resorption (8.7%) and malformations (8%) in control group. The malformations include cranial defect and exencephaly (100%), micrognathia and tongue extrusion (100%), limb defects (40%), renal pelvic dilatation (39%), and cleft palate (15%). Interestingly, BHA induced GSTs activities by 62% and 46% over the control in liver and placenta, respectively, and remarkably reduced the fetal resorption (13.9%) and malformations, resulting in 62% of cranial defect and exencephaly, 68% of micrognathia and tongue extrusion, 29% of limb defects, and 14% of renal pelvic dilatation. Taken together, it is suggested that a long-term pretreatment with BHA could substantially prevent fetuses from abortion and malformations following intrauterine exposure to teratogens including cyclophosphamide by inducing phase II antioxidant enzymes such as GSTs.
Effect of BNs-3 and BNs-7, Extracts of Citrous Orange Peel, on the Obesity Induced by ad libitum Feeding a Cholesterol-Containing Diet in Rats
Toxicological Research, volume 19, issue 3, 2003, Pages 189~195
The protective effects of BNs-3 and BNs-7, extracts of citrous orange peel, on the obesity induced by ad libitum feeding a cholesterol-containing diet to rats were investigated. The animals were fed on the diet including cholesterol (0.5%) with or without the citrous orange peel extracts BNs-3 (5%) and/or BNs-7 (0.1%) for 8 weeks. The ad libitum feeding a diet containing cholesterol to rats from 6 weeks of age increased the body weight gain compared with that of rats fed on a normal diet. Such an increase in body weights was markedly attenuated by the addition of BNs-3 or BNs-7 to the diet. Especially, a combinational feeding on BNs-3 and BNs-7 significantly reduced the body weight gain below that of normal diet-fed animals. Interestingly, the weights of abdominal adipose tis-sues surrounding epididymides were greatly reduced by the citrous orange peel extracts, in parallel with the decrease in body weights. In addition, blood concentrations of lipids including cholesterol were also lowered by the combinational treatment with BNs-3 and BNs-7. Taken together, it is suggested that the obesity and overweight produced by unrestricted overfeeding on diet with cholesterol may be partially due to the accumulation of abdominal adipose tissues, around the epididymides in rats, and that citrous orange peel extracts might exert antiobese activities by reducing the adipose tis-sues as well as blood lipid concentrations.
Apicidin-Mediated Apoptosis Signaling in Human Promyelocytic Leukemia U937 Cells
Toxicological Research, volume 19, issue 3, 2003, Pages 197~203
Apicidin, a histone-deacetylase inhibitor, has been successfully used to inhibit the growth of cancer cells. In this study, the apoptotic potential and mechanistic insights of apicidin were investigated in human myeloid leukemia U937 cells. Treatment of U937 cells with apicidin resulted in a decrease of cell viability with apoptotic characteristics, including chromatin condensation and ladder-pattern fragmentation of genomic DNA. Apicidin converted the procaspase-3 protease to catalytically active effector protease, resulting in subsequent cleavage of poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, apicidin induced the activation of caspase-9 protease and the cytosolic release of mitochondrial cytochrome c with mitochon-drial membrane potential transition. Moreover, apicidin transiently increased the expression of Fas and Fas ligand proteins. Taken together, the results suggest that apicidin induces apoptosis of U937 cells through activation of intrinsic caspase cascades and Fas/FasL system with mitochondrial dysfunction.
Association between I/D Polymorphism of Human LRPAP1 Gene and Body Mass Index in Korean General Population
Kang, Byung-Yong ; Bae, Hak-Gyoon ; Jhin, Hae-Kyung ; Lee, Kyung-Soon ; Lee, Kang-Oh ;
Toxicological Research, volume 19, issue 3, 2003, Pages 205~210
The aim of this study was to estimate the influence of 37 bp insertion/deletion (I/O) poly-morphism of the low density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) gene on anthropometrical or biochemical parameters in korean general population. To determine the frequency of the genotype, we analyzed 244 samples of Korean origin. The frequency of the I allele was 0.55 in men and 0.56 in women, which were significantly higher than the frequency (0.26) that was reported in Czech population of Caucasian origin. In addition, the I allele of this polymorphism was significantly associated with higher value of body mass index (BMI) in our subjects by ANOVA test (P<0.05), and this association was maintained after controlling for age and gender by ANCOVA test (P<0.05). Thus, our results suggest that the I/O polymorphism of the LRPAP1 gene may be useful as a genetic marker for obesity in Korean general population.
Acute Oral Toxicity of Extract Derived from Fruiting Body of Phellinus gilvus in Rats
Bae, Jae-Sung ; Jang, Kwang-Ho ; Park, Sung-Guk ; Jo, Woo-Sik ; Rhee, Man-Hee ; Kwon, Oh-Deog ; Kim, Young-Hoan ; Kim, Eun-Young ; Park, Seung-Chun ;
Toxicological Research, volume 19, issue 3, 2003, Pages 211~215
This study was carried out to investigate the acute oral toxicity of a crude extract derived from fruiting body of Phellinus gilvus (PGE) using male and female SD rats. Groups consisted of five male and female rats were treated with a single dose of the test substance intragastrically at 0, 500, 1,000, 2,000, and 5,000 mg/kgaj, respectively. Clinical signs, body weight change, and food and water consumption change were observed for 14 days after administration. No mortality or abnormal clinical signs in animals were shown during the observation period at the dose used in this study. Also there was no difference in net body weight gain, water and food consumption or gross pathological findings at terminal sacrifice among the groups of rat treated with different doses of the test substance. The results suggested that acute oral toxicity of PGE in rats is very low at the conditions employed in this study and
of PGE was estimated to be over 5,000 mg/
in both sexes of rats.
In Vivo Cytotoxicity of Lead Acetate: Changes of Plasma DNA Content and Blood Biochemical Values in Rats
Toxicological Research, volume 19, issue 3, 2003, Pages 217~225
Changes of plasma DNA contents and serum biochemical values were measured in rats administered with lead acetate to investigate the in vivo cytotoxic effects of lead and examine the usefulness of these in vivo cytotoxicity changes as indicators of lead exposure and diagnosis of lead poisoning. Rats were given once intraperitonealy with lead acetate (1.6, 8, 40 and 200 mg/kg b.w) and the changes of plasma DNA contents and serum biochemical values were measured at the time of 2, 4, 8, 24, 48 and 72 hours after the administration of lead acetate. Plasma DNA contents began to increase at 2 hours after the administration of lead acetate in the treatment groups of 8, 40 and 200 mg/kg b.w dose-dependently and significantly compared with control group. These DNA increases of each dosage group were continued until 24, 48 and 72 hours and the maximum levels of DNA (4.02, 10.67 and 14.10 times of control) were arrived at 8, 8 and 4 hours after the each treatment, respectively. Among 10 serum biochemical indicators, the activities of creatine kinase were increased to maximum level (6.55 times of control) at 2 hours after the administration and remained to be significantly higher than that of control by 8 hours in the treatment group of 200 mg, however, after 48 hours, the levels in the treatment groups of 40 mg above were lower than that of control. The values of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were higher than that of control from 2 to 24 hours in the treatment group of 200 mg. Maximum levels of these enzymes were 3.34, 3.00 and 3.19 times of control, respectively. Both of alkaline phosphatase and triglyceride values in the treatment groups were decreased compared with control. In the case of alka-line phosphatse, the values were significanly decreased from 24 hours and more severely decreased until 72 hours in the treatment groups of 40 mg above (p<0.01). The minimum value was 0.36 times of control in the 200 mg group. The values of triglyceride were significantly decreased in the tratment groups of 40 mg above (p<0.01), but the values were not different significantly among the treatment groups. This study demonstrates that plasma DNA content and serum biochemical values such as aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase and triglyceride are valuable as biomarkers for exposure assessment and diagnosis of lead poisoning.
Assessment of Embryotoxicity of 2-Bromopropane in ICR Mice
Kim, Jong-Choon ; Shin, Dong-Ho ; Kim, Sung-Ho ; Oh, Ki-Seok ; Kim, Hyeon-Yeong ; Her, Jeong-Doo ; Jiang, Cheng-Zhe ; Chung, Moon-Koo ;
Toxicological Research, volume 19, issue 3, 2003, Pages 227~234
2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones (CFCs) which have a great potential to destroy the ozone layer and to warm the earth's environment. The present study was undertaken to evaluate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure during the gestational days (GD) 6 through 17 in ICR mice. The test chemical was administered subcutaneously to pregnant mice at dose levels of 0, 313, 625 or 1,250 mg/kg/day. All dams were subjected to caesarean section on GD 18 and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1,250 mg/kg group, maternal toxicity included an increase in the incidence of abnormal clinical signs and a decrease in the maternal body weight, body weight gain, and corrected body weight. Developmental toxicity included a decrease in the fetal body weight, a reduction in the placental weight, an increase in the fetal skeletal variation and ossification delay. There were no adverse effects on either pregnant dams or embryo-fetal development in the 313 and 625 mg/kg groups. These results suggest that a 12-day subcutaneous dose of 2-BP is embryotoxic at a maternally toxic dose (i.e., 1,250 mg/kg/day) in ICR mice. In the present experimental condition, the no-observed-adverse-effect level of 2-BP is considered to be 625 mg/kg/day for dams and embryo-fetuses, respectively.
Differential Role of Ethanol, Glycerol, 4-Methylpyrazole and Isoniazid on Human CYP2E1 Activity in Intact HepG2 Cells
Toxicological Research, volume 19, issue 3, 2003, Pages 235~240
The modification of CYP2E1 activity is of considerable interest because of its role in the metabolic activation of a variety of toxic chemicals. In the present studies, the time-course of changes in human CYP2E1 activities was determined after treatment with ethanol, glycerol, 4-methylpyrazole or isoniazid using intact HepG2 cells transfected by human CYP2E1. Hydroxylation of chlorzoxazone was chosen for the measurement of CYP2E1 activity. CYP2E1 protein levels were increased upon cultivation of cells in the presence of ethanol, glycerol, 4-methylpyrazole or isoniazid for 24 hr. After 24 hr cultivation, ethanol or glycerol increased CYP2E1 activities, whereas 4-methylpyrazole or isoniazid inhibited. This different effect of the chemical inducers on CYP2E1 activi-ties persisted to subsequent 24 hr. Competitive inhibition study suggested that 4-methylpyrazole or isoniazid has stronger binding affinity to CYP2E1 than ethanol or glycerol. These results demonstrate that different binding affinity of the chemical inducers to the active site of CYP2E1 plays important role in determining real CYP2E1 activity in intact cells after treatment with the chemical inducers. Present study would be helpful in precise understanding of human CYP2E1-mediated toxicity.
Acute Oral Toxicity of Paecilomyces sinclairii in Beagle Dogs
Toxicological Research, volume 19, issue 3, 2003, Pages 241~245
The acute toxicity of Paecilomyces sinclairii was tested in beagle dogs. We daily examined clinical signs, body weights, and hematological/biochemical examinations for 14 days after administration of Paecilomyces sinclairii with different dose levels (0, 0.4, 2 and 10 g/kg). There were no clinical signs and no significant changes in hematological and biochemical analysis. These results showed that Paecilomyces sinclairii did not induce any remarkable acute toxic response and the
was greater than 10 g/kg in beagle dogs.
Cancer Gene Therapy. History and Major Developments
Toxicological Research, volume 19, issue 3, 2003, Pages 247~257
Medicine is undergoing a revolution in the understanding of the mechanisms through which disease processes develop. The advent of genetics and molecular biology to oncology not only is providing surrogate predictors of therapy response and survival which are forming the basis for selection among established treatment options, but is providing targets for new directions in therapy as well. Molecular modification of somatic cells for the purposes of protecting the normal cells from the toxicity of cancer chemotherapy, for the sensitization of the tumor cells to therapy and use of conditionally replicating viral vector have been new directions of cancer treatment which have reached the clinical arena. Advances in molecular pharmacology and vector design summarized in this paper may provide solutions to some of the existing problems in the technology of gene transfer therapy. Continued basic research into the biological basis of human disease, systemic studies of the application of these discoveries to therapy and the improvement of vector for gene delivery all combined may result in advances in this important field of therapy over the next few years.