• Molecular & Cellular Toxicology
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• v.1 no.1
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• pp.32-39
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• 2005

Polycyclic aromatic hydrocarbons (PAHs) are an important class of environmentally prevalent xenobiotics that exert complex effects on the biological system and characterized as probably carcinogenic materials. Single cell gel electrophoresis assays were performed in order to evaluate DNA damage occurring in the T-and B lymphocytes, spleens (T/B-cell), bone marrow, and livers of mouse exposed to mixture of PAHs (Benzo(a)pyrene, Benzo(e)pyrene, Fluoranthene, Pyrene) at dose of 400, 800, or 1600 mg/kg body weight for 2 days. DNA damage of the cells purified from mice was increased in dose dependent manner. In the blood cells and organs, DNA damage was also discovered to vary directly with PAHs. Especially T-cells had been damaged more than B-cell. Plasma proteomes were separated by 2-dimensional electrophoresis with pH 4-7 ranges of IPG Dry strips and many proteins showed significant up-and -down expressions with the dose dependent manner. Of these, significant 4 spots were identified using matrix-assisted laser desorption/ionization-time of fight (MALDI-TOF) mass spectrometry. Identified proteins were related to energy metabolism and signal transduction.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.129-130
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• 1994

The science of toxicology is the understanding of the mechanisms by which exogenous agents produce deleterious effects in biological systems. The actions of chemicals such as drugs are ultimately exerted at the cellular and gene levels. Over the past decade. several in vitro alternative methods such as cultured cells for assessing the toxicity of various xenobiotics have been proposed to reduce the use of animals. In this workshop three advanced methods will be presented. These methods are novel important models for toxicologic studies. Dr. Tabuchis group has establishcd two immortalized gastric surface mucosa cell lines from the pminary cultore of gastric fundic mucosal cells of adult transgenic mice harboring a temperature sensitive simian virus 40 large T-anugen gene. As the immortalized cell lines of various tissues possess unique characteristics to maintain their normal functions for several months, these cell lines are extremely useful for not only toxicity testing but also pharmacological screening in new drug development. Professor Funatsu have studied the formation of spherical multicelluar aggregates of adult rat hepatocytes(spheroid) having tissue like structure. The sphcroid shown thre is a prototype module of an artificial liver support system. Thus, the urea synthesis activity of the artificial liver was maintained at least to days in 100％ rat blood plasma. Dr. Takezawa and his coworkers have developed a novel culture system of multicellular spheroids considered 〃organoids〃 by utilizing a thermo-responsive polymer as a substratum of anchorage dependent cells. His final goal is to reconstitute the organoids of various normal organs, e.g., liver, skin etc. and also abnormal deseased organs such as tumor.

• Environmental Mutagens and Carcinogens
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• v.22 no.4
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• pp.324-330
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• 2002

Bisphenol A (BPA) is a monomer widely used in the manufacturing polycarbonate plastics or epoxy resin, and xenobiotics recently known as endocrine disrupting chemical. In this paper, to assess the effects of bisphenol A on immunopathological parameters (body weight, organ weight, hematological parameters, cellularity and surface marker) in mice, ICR female mice were orally exposed to BPA dissolved in olive oil as concentrations of 100, 500, 1000 ㎎/㎏/day b.w. 5 days a week for 30 days (subacute exposure). Liver - and kidney weight was significantly increased as dose-dependent manner, but body- , spleen- and thymus- weight didn't changed. In hematological parameters, WBC and MCHC were lowered but HCT and MCV were siginificantly enhanced. There was no significant differences in peritoneal macrophages number of the mice exposed to BPA. However, number of splenocytes of spleen, CD3/sup +/ and CD4/sup +/ cell in splenocytes, CD4/sup +/ and CD8/sup +/ cell in thymocytes were decreased at the mice subacutely exposed to BPA. In addition, BPA decreased expression of B7-1 and B7-2 on macrophages. Therefore, these results showed BPA may affect hematological parameters, cellularity and surface marker of immunocytes.

• Environmental Mutagens and Carcinogens
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• v.22 no.4
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• pp.274-278
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• 2002

Phthalates, suspected endocrine disruptor, are plasticizer and solvent used in industry, and some phthalates are known as potential carcinogen. Most common human exposure to this compounds may occur with contaminated food. It may migrate into food from plastic wrap or may enter food from general environmental contamination, and it has become widespread environmental pollutants, thus leading to a variety of phthalates that possibly threaten the public health. Dibutyl phthalate (DBP) may playa part of cell proliferator, which mediates changes in gene expression and the metabolism of xenobiotics. An understanding of the role of DBP in modulating gene regulation should provide insight regarding mechanisms of DBP induced xenoestrogenic impact. To elucidate the type of genes that are associated with estrogenic activity induced by DBP at the dose (10$^{-8}$ M) appeared proliferating effects, the pattern of gene expression in MCF7 cells was compared between 17$\beta$-estradiol and DBP exposure in the cDNA microarray. From the results, it showed some differences of gene expression patterns between MCF7 cells treated with 17$\beta$-estradiol and DBP, and also DBP shows estrogenic potential with changes in estrogen-related gene expression levels.

• Biomedical Science Letters
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• v.8 no.3
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• pp.155-159
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• 2002

To evaluate the physiological significance of xanthine oxidase (XO) in rat skin, the activity of XO (type O) in skin was compared with that of small intestine or liver. Concomitantly, XO activities in some partial portions (scalp, leg, dorsal and ventral part) of skin were determined and then compared with each partial portion. XO activity of skin was lower than that of small intestine and rather higher than that of liver. Furthermore, the activity of XO in skin, after clipping of hairs and then in 5 days, was more increased than that of rat which was clipped before having been sacrificed. As for activities of free radical scavenging system (GPx, GST, SOD), skin is lower than liver and small intestine. Although it is hewn that the oxygen free radical generated by XO system lead to injurious effect on the cell, the XO activity of ventral part which is to be less exposed to xenobiotics and biological agents was the lowest among those of ventral, dorsal, leg and scalp parts in skin. In conclusion, it may be hypothesized that XO system in skin act on defence mechanism.

• Toxicological Research
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• v.17
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• pp.83-88
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• 2001

Most reactive oxygen species (ROS) are free radicals and implicated in the development of a number of disease processes including artherosclerosis, neurodegenerative disorders, aging and cancer. ROS are byproducts of a number of in vivo metabolic processes and are formed deliberately as part of nor-mal inflammatory response. On the other hand, ROS are generated either as by products of oxygen reduction during xenobiotic metabolism or are liberated as the result of the futile redox cycling of the chemical agents including several chemical carcinogens. A better understanding of the mechanisms of free radical toxicity may yield valuable clue to risks associated with chemical exposures that leading to the development of chronic diseases including cancer. The molecular biology of ROS-mediated alterations in gene expression, signal transduction and carcinognesis is one of the important subjects in free radical toxicology. Epidemiological studies suggest that high intake of vegetables and fruits are associated with the low incidence of human cancer. Many phytopolyphenols such as tea polyphenols, curcumin, resveratrol, apigenin, genistein and other flavonoids have been shown to be cancer chemopreventive agents. Most of these compounds are strong antioxidant and ROS scavengers in vitro and effective inducers of antioxidant enzymes such as superoxide dismutatse, catalase and glutathione peroxidase in vivo. Several cellular transducers namely receptor tyrosine kinase, protein kinase C, MAPK, PI3K, c-jun, c-fos, c-myc, NFkB, IkB kinase, iNOS, COX-2, Bcl-2, Bax, etc have been shown to be actively modulated by phyto-polyphenols. Recent development in free radical toxicology have provided strong basis for understanding the action mechanisms of cancer chemoprevention.

• Toxicological Research
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• v.17
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• pp.299-304
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• 2001

Xenobiotics and their reactive intermediates bind to cellular macromolecules and/or generate oxidative stress. which provoke deleterious effects on the cell function. Induction of xenobiotic-biotrans-forming enzymes and antioxidant molecules is an important defense mechanism against such insults. A group of genes involved in the defense mechanism. e.g. genes encoding glutathione S-transferases. NAD(P)H: quinone oxidoreductase, UDP-glucuronosyltransferase (UDP-GT) and ${\gamma}$-glutamylcysteine synthetase (GGCS). have a common regulatory sequence, Antioxidant or Electrophile Responsive Element (ARE/EpRE). Recently. Nrf2. discovered as a homologue of erythroid transcription factor p45 NF-E2, was shown to bind ARE/EpRE and induce the expression of these defense genes. Mice that lack Nrf2 show low basal levels of expression and/or impaired induction of these genes. which makes the animals highly sensitive to xenobiotic toxicity. Indeed. we show here that nrf2-deficient mice had a higher mortality than did the wild-type mice when exposed to acetaminophen (APAP). Detailed analyses of APAP hepatotoxicity in the nrf2 knockout mice indicate that a large amount of reactive APAP metabolites was generated in the livers due to the impaired basal expression of two detoxifying enzyme genes, UDP-GT (Ugt1a6) and GGCS. while the cytochrome P450 content was unchanged. Thus. the studies using the nrf2 knockout mice clearly demonstrate significance of the expression of Nrf2-regulated enzymes in protection against xenobiotic toxicity.

• Environmental Analysis Health and Toxicology
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• v.24 no.3
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• pp.213-218
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• 2009

1-bromopropane (1-BP) has been used in numerous purposes such as an intermediate in the synthesis of pharmaceuticals, a solvent for fats, waxes, or resins and a substitute for chlorofluorocarbons that destroy the ozone layer. However, the studies related to the modulation of activities of hepatic cytochrome P450s (CYPs) are not reported yet. This study was the first study to investigate the potential effect for the activities of hepatic CYPs by the treatment of 1-BP in vivo. When 1-BP was treated to male ICR mice by dose-dependently at the dose levels of 200, 500 and 1,000 mg/kg of body weight once, the activity of CYP2E1 was selectively increased for 24 h. The inductive potency for the activity of CYP2E1 by 1-BP was equal to induction by acetone a well-known selective CYP2E1 inducer. The present results indicated that 1-BP would affect the metabolism of 1-BP itself and/or other xenobiotics.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2839-2843
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• 2015

Background: MDR1, one of the most important drug-transporter genes, encodes P- glycoprotein (P-gp)-a transporter involved in protecting against xenobiotics and multi-drug resistance. The significance of the genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Materials and Methods: To evaluate whether C3435T and C1236T MDR1 polymorphisms are associated with the occurrence and outcome of ALL, 208 children with ALL (median age 5.0 yr) and 101 healthy Thai children were studied by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assay. Results: C3435T and C1236T MDR1 polymorphism are significantly associated with the high-risk group (OR= 2.6, 95%CI =1.164-5.808; P=0.028 and OR= 2.231, 95%CI =1.068-4.659; p=0.047, respectively), indicating that both may be candidates for molecular markers in the high-risk group of ALL.

• Journal of Aquaculture
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• v.18 no.3
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• pp.200-206
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• 2005

We previously pointed out that the polluted sediment elutriate manifestly affected the early events of reproductive outputs in the Pacific oysters, Crassostrea gigas. A serial dilution of priority xenobiotic sediment elutriates determined by gas chromatography/mass spectrometry (GC/MS) were exposed to gametes of the oyster with different stress burdens to detail the maternal stress transfer to its reproductive outputs. There was an apparent critical concentration over which survival and morphogenesis were significantly affected with more profound damage in morphogenesis. The critical concentration which drives mortality and abnormal morphogenesis of the larvae corresponded to a dilution between 10 and 20% of our elutriate. The adverse effects of the early lives by the xenobiotic exposure over the critical concentration were magnified by the maternal stress from the exposed benzo(a)pyrene (BaP), one of the priority polyaromatic hydrocarbons (PAHs) during the maturation condition. These results indicate that maternal transfer of the xenobiotic compounds from oysters living in the contaminated location might represent a significant adverse effect to their larval population of wild seeds.