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랫드에서 고환독성의 정색을 위한 정량적 평가법의 확립: 2-bromopropane의 예
차신우,배주현,손우찬,신진영,신동호,김성호,박승춘,김종춘,Cha Shin-Woo,Bae Joo-Hyun,Son Woo-Chan,Shin Jin-Young,Shin Dong-Ho,Kim Sung-Ho,Park Seung-Chun,Kim Jong-Choon 한국생명과학회 2005 생명과학회지 Vol.15 No.3
The aims of the study were to establish a short-term screening test for detecting testicular toxicity of chemicals in rats and to determine whether a 2-week administration period is sufficient to detect testicular toxicity of 2-bromopropane (2-BP) as an example. Male Sprague-Dawley rats were subcutaneously administered with 1000 mg/kg/day of 2-BP or its vehicle for 2 weeks. Ten male rats each were sacrificed on days 3, 7 and 14 after the initiation of treatment. Parameters of testicular toxicity included genital organ weights, testicular sperm head counts, epididymal sperm counts, motility and morphology, and qualitative and quantitative histopathologic examinations. The early histopathological changes observed on day 3 of treatment included degeneration of spermatogonia and spermatocytes, multinuclear giant cells, mature spermatid retention, vacuolization of Sertoli cells, and decreased number of spermatogonia in stages II and V. On day 7 of treatment, atrophy of seminiferous tubules, exfoliation of germ cells, degeneration of spermatogonia and spermatocytes, multinuclear giant cells, mature spermatid retention, vacuolization of Sertoli cells, decreased number of spermatogonia in stages II and V, and decreased number of spermatocytes in stages VII and XII. On day 14 after treatment, a significant decrease in the weights of testes and seminal vesicles was found. Atrophy of seminiferous tubules, exfoliation of germ cells, degeneration of spermatogonia and spermatocytes, mature spermatid retention, vacuolization of Sertoli cells, decreased number of spermatogonia in stages II and V, and decreased number of spermatocytes in all spermatogenic stages were also observed. In addition, a slight non-significant decrease in testicular sperm head counts, daily sperm production rate and epididymal sperm counts was found. The results showed that 2 weeks of treatment is sufficient to detect the adverse effects of 2-BP on male reproductive organs. It is considered that the short-term testicular toxicity study established in this study can be a useful tool for screening the testicular toxic potential of new drug candidates in rats.
Type IV phosphodiesterase inhibitor ( CJ-10882 ) 의 개에 대한 2 주간 경구반복투여 독성시험
차신우(Shin Woo Cha),배주현(Ju Hyun Bae),김종춘(Jong Choon Kim),김달현(Dal Hyun Kim),이근호(Koun Ho Lee),한정희(Jung Hee Han),송석범(Seog Beom Song) 한국응용약물학회 2002 Biomolecules & Therapeutics(구 응용약물학회지) Vol.10 No.2
N/A CJ-10882, (E)-[(3-Cyclopentyloxy-4methoxyphenyl)methylene]hydrazine-carboxamide, is a newly developed type IV phosphodiesterase isozyme (PDE IV) inhibitor. To investigate the subacute toxic effects of CJ-10882, it was administered to both male and female dogs at 0, 25, 50, 100 or 200 ㎎/㎏/day orally for up to 2 weeks. During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross finding, organ weight, and histopathology were evaluated. Several clinical signs were observed in treated dogs at above 25 ㎎/㎏, including salivation and vomiting. A reduction in the body weight was observed in both sexes at above 50 ㎎/㎏. There were no treatment-related effects on mortality, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings, and histopathology in any treatment group. The results of this study demonstrate that CJ-10882, a selective inhibitor of the type IV class of PDE, may cause effects on gastrointestinal tract and salivary glands. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors.
Cha, Shin Woo,Gu, Hee Kyoung,Lee, Ki Poong,Lee, Mun Han,Han, Sang Seop,Jeong, Tae Cheon 영남대학교 약품개발연구소 2000 영남대학교 약품개발연구소 연구업적집 Vol.10 No.-
Ethyl carbamate, a potent carcinogen, has been characterized to be metabolized by cytochrome P450(P450) and esterase. It has recently been demonstrated that P450 may activate ethyl carbamate to immunotoxic metabolites. To investigate the role of esterase in ethyl carbamate-induced immunosuppression, mice were pretreated intraperitoneally with an esterase inhibitor, diazinon, at 20 ㎎/㎏ 30min prior to the administration of ethyl carbamate intraperi-toneally at 100 and 400㎎/㎏ for 7 consecutive days. Pretreatment with diazinon completely blocked the serum esterase activity. Histopathologically splenic and thymic atrophy was observed when mice were treated with ethyl carbamate, which was potentiated by he pretreatment with diazinon. In spleen, lymphocytes in the periarteriolar lymphoid sheath and the marginal zone appeared to be depleted in the white pulps. In thymus, ethyl carbamate caused a marked depletion of cells in cortex. The antibody response to sheep red blood cells(SRBCs) was more suppressed by ethyl carbamate in diazinon-pretreated groups. These results suggest that the metabolism of ethyl carbamate by esterase may be an inactivation pathway in ethyl carbamate-induced immunosuppression. In addition, ethyl N-hydroxycarbamate, a P450 metabolite, suppressed the lymphoproliferative response induced by lipopolysaccharide and concanavalin A in splenocyte cultures. These results indicate that the metabolism of ethyl carbamate by P450 may be an activation pathway in immunosuppression by ethyl carbamate. ⓒ 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.
Role of corticosterone in ethyl carbamate-induced immunosuppression in female BALB/c mice
Cha, Shin Woo,Lee, Hu Jang,Cho, Myung Haing,Lee, Mun Han,Koh, Woo Suk,Han, Sang-Seop,Kim, Jung-Ae,Lee, Eung-Seok,Nam, Doo-Hyun,Jeong, Tae Cheon 영남대학교 약품개발연구소 2001 영남대학교 약품개발연구소 연구업적집 Vol.11 No.-
We have recently demonstrated that the antibody response to the T-cell-dependent antigen, sheep red blood cells(SRBCs), was suppressed by ethyl carbamate in female BALB/c mice. At the same doses, ethyl carbamate decreased in the numbers of splenic macrophages. B cells, total T cells, CD4^(+) T cells and CD8^(+) T cells. In addition, the serum level of corticosterone was increased dose-dependently. To investigate the possible role of corticosterone in ethylcarbamate-induced immunosuppression, the antibody response to SRBCs and the subpopulation changes of splenocytes and thymocytes were determined in naive, sham-operated and adrenalectomized (ADX) female BALB/c mice. When the mice were treated intraperitoneally with 400 mg/kg ethyl carbamate, the antibody response was significantly suppressed by ethyl carbamated in naive and sham-operated mice in accompanying the decrease in spleen and thymus weights and/or the increase in the level of serum corticosterone. Meanwhile, the antibody response was not suppressed by ethyl carbamate in the ADX mice. The splenic numbers of total cells, macrophages B and T cells, and CD4^(+) cells were decreased by ethyl carbamate in naive and sham-operated mice. Meanwhile, each cell number was comparable with control in the ADX mice. The flow cytometric analyses on thymocytes did not show obvious differences as seen in the spleen. Finally, when the ADX mice were treated intraperitoneally with 25 mg/kg corticosterone, the antibody response was significantly suppressed. Taken together, our present results suggested that corticosterone might be, at least partially, responsible for ethy; carbamate-induced immunosuppression in female BALB/c mice. ⓒ 2001 Elsevier Science Ireland Ltd. All rights reserved.
비글견에 있어서 새로운 안트라싸이클린계 항암제 DA-125의 정소독성연구
김종춘,차신우,송시환,정문구,Kim, Jong-choon,Cha, Shin-woo,Song, Si-whan,Chung, Moon-koo 대한수의학회 1997 大韓獸醫學會誌 Vol.37 No.2
To assess the testicular toxicity induced by DA-125, a new anthracycline anticancer agent, the test substance was intraveneously administered to male beagle dogs at dose levels of 0, 0.0023, 0.0375, 0.15, and 0.6 mg/kg/day, 6 days a week for 26 weeks. At 0.6 mg/kg/day, 1 out of 3 dogs had died on day 42 of treatment and the other dogs were sacrificed on days 46 and 122 of treatment due to the increasingly severe clinical condition. Clinical signs considered to be related to treatment were included anorexia, vomiting, salivation, decreased activity, mucous and/or dark faeces, diarrhea, and swelling, abscess and/or ulceration of injection sites. Suppression in body weight gain, reduction in food intake, decreases in testicular weight and size, and hemorrhage of epididymis were also observed in male dogs. Microscopically, severe degenerative changes such as atrophy of seminiferous tubules, loss of germ cells, degeneration of germ cells, vacuolization of Sertoli cells, and hyperplasia of Leydig cells were observed in all dogs. Azoospermia in epididymal tubules, atrophy of epithelia in the cauda epididymis, and prostate atrophy were also found. At 0.15 mg/kg/day, anorexia, vomiting, salivation, diarrhea, and swelling of injection sites were observed. In addition, suppression in body weight gain and decreases in testicular weight and size were found in male dogs. Atrophy of seminiferous tubules, decrease of germ cells, degeneration, exfoliation and retention of germ cells, vacuolization of Sertoli cells, and hyperplasia of Leydig cells were observed by histopathological examination. Azoospermia in epididymal tubules and prostate atrophy were also found. At 0.0375 mg/kg/day, there were no clinical signs considered to be indicative of a reaction to treatment, but testicular size was significantly reduced. Microscopically, decreases in the number of spermatogonia and epidydimal speramtozoa were found. There were no evidences of general or testicular toxicity at 0.0023 mg/kg/day. These results indicate that DA-125 produces significant and persistent damage to the spermatogenic compartments of the testes in male beagle dogs.
신호철,차신우,배주현,김현주,정태천,박종일,윤종만,김계웅,김진석,한상섭,Shin, Ho-chul,Cha, Shin-woo,Bae, Ju-hyun,Kim, Hyun-ju,Jeong, Tae-cheon,Park, Jong-il,Yoon, Jong-man,Kim, Gye-woong,Kim, Jin-suk,Han, Sang-seop The Korean Society of Veterinary Science 1996 大韓獸醫學會誌 Vol.36 No.1
Dihydrofolate reductase(DHFR) 억제제는 혈중활성엽산유도체의 농도저하를 초래하는데 이에 대한 기전을 밝히고자 DHFR 억제제의 대표적 약물로서 항암치료에 널리 사용되고 있는 methotrexate를 0.3 및 10mg/kg의 용량으로 랫드에 정맥주사한 후 활성엽산유도체의 담즙배설동태를 검토하였다. 임상적용 용량을 상회하는 용량임에도 불구하고 methotrexate에 의한 환원형엽산유도체의 담즙배설은 유의적 감소를 나타내지 않았다. 이러한 결과는 methotrexate에 의한 엽산유도체의 혈중농도저하가 활성엽산유도체의 담즙배설저하에 직접 관련되지 않는 것을 나타낸다. 따라서 장간순환계가 체내 엽산대사 및 항상성 유지에 중심기구임을 고려해 볼 때 DHFR 억제제에 의한 활성엽산유도체의 혈중농도저하는 담즙배설의 변화에 의한 것 보다는 소화관에 배설된 후 재흡수의 저하에 의해 초래될 가능성이 높은 것으로 사료된다. The biliary excretion kinetics of the active folate derivatives were examined after an intravenous injection of methotrexate at doses of 0.3 and 10mg/kg to clarify the mechanism of the acute decrease in the plasma folate by the dihydrofolate reductase inhibitors. Even at a higher dose than used in the clinical therapy, methotrexate did not cause any acute depletion of folate denvatives in the excreted bile. Therefore, the decrease in the plasma folate appeared not to be related with the biliary excretion process of folates. A factor responsible for the plasma folate depletion by DHFR inhibitors may be due to the malabsorption of folate derivatives excreted into the small intestine.