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황산구리 투여 백서에 비타민 A 및 부신적출이 미치는 영향에 관한 형태학적 연구

Other Titles
 Morphlolgical Effect of Copper Sulfate on the Rat:Influences of Vitamin A and Adrenalectomy 
Issue Date
1972
Description
의학과/박사
Abstract
[한글] Morphological Effect of Copper Sulfate on the Rat: Influences of Vitamin A and Adrenalectomy Hong Yul Choi, M.D. Department of Medical Science, The Graduate School, Yonsei University (Directed by Prof. Dong Sik Kim, M.D. and Prof. Yoo Bock Lee, M.D.) Wilson's disease is one of the genetic disorders leading to the accumulation of excessive amount of copper, which in time causes pathologic changes in the patient's liver, brain, kidney, and cornea. Deficiency or absence of serum ceruloplasmin and elevated concentrations of hepatic copper are both characteristic and diagnostic abnormalities which precede the appearance of histopathologic hepatic changes(Goldfischer and Sternlieb, 1968). However, studies on the concentration of ceruloplasmin over the past two decades, have not provided a unified concept of all the abnormalities observed in this disease, although it provided an enormous amount of clinically useful data. And the mechanism by which copper exerts its toxic effect on the hepatic cells in Wilson's disease is unknown yet. Attempts to prodcue hepatic dysfunction and morphologic lesions equivalent to Wilson's disease in experimental animals have been unsuccessful. For example experimentally induced deposits of copper in hepatic cell generally do not produce necrosis (Howell, 1959; McNary, 1963; Barka, et al., 1964). Recently, results of many experiments on this subject suggested that sequestration of copper by lysosomes, may protect hepatocytes from toxic effects of the metal (Goldfischer and Moskal, 1966; Goldfischer, 1967; Goldfischer and Sternlieb, 1968; Goldfischer, et al., 1970). The present investigation was carried out to investigate wlether vitamin A administration and adrenalectomy, which are known to labilize and stabilize lysosomal membrane respectively, influence on copper toxicity in various organs, such as the liver, spleen and adrenal gland of the rat. Meterials and Methods Adult female albino rats were divided into five groups and treated as follows: Group Ⅰ: Normal control 16 rats Group Ⅱ: CuSo^^4 treated 16 rats Group Ⅲ: Vitamin A treated 16 rats Group Ⅳ: CuSo^^4 and vitamin A treated 20 rats Group Ⅴ: Adrenalectomy and CuSo^^4 treated 20 rats 0.3cc of 0.5% copper sulfate solution was given intraperitoneally per animal daily. Vitamin A was administered orally in a dose of 500 I.U. per gram of body weight daily. In group Ⅳ, animals were treated with copper sulfate for 5 days prior to combining treatment of copper sulfate and vitamin A. In group Ⅴ, a bilateral adrenalectomy was done and the animals were maintained with 1% saline solution. Copper sulfate treatment began 2 weeks after the adrenalectomy. At 3rd, 7th, 10th and 15th days, 4∼5 rats were killed by exanguination. Speciments for light microscopic studies were fixed in 10% neutral formalin and embedded in paraffin. Sections, 6 micron thick, were made and stained with hematoxylin and eosin routinely. Additionally, sodium diethyldithiocarbamate stain (Howell, 1959), oil red O stain, periodic acid Schiff reaction after diastase treatment, Gomori's iron reaction with the liver sections, Gomori's iorn reaction with the spleen sections, and oil red O stain with the adrenal sections were performed. Specimens for electron microscopic studies were obtained from the liver only. The specimens were cut in 1mm**3 in size and fixed in 1% osmic acid in phosphate buffer at pH 7.4, and embedded in Epon 812. After staining with uranyl acetate and lead hydroxide, an observation was made with a Hitachi HY 11-E model electron microscope. Result and Summary The results may be summerized as follows: 1) Neither marked necrosis, nor cirrhotic change of the liver was induced with copper sulfate only. But in the adrenal gland, increase in size and hyperplastic changes of zona fasciculats and zona reticularis were observed with an increased amount of fatty substances. 2) Large amounts of vitamin A administration induced inflammatory and necrotic changes in the liver. However, previous and combined treatment with copper sulfate could prevent this toxic effect of vitamin A on the liver. 3) Copper sulfate treatment to the adrenalectomized rat induced focal necrosis and an increase in hepatic cell mitoses which was very similar to the regenerative changes, and the copper accumulation was sightly accentuated compared to non-adrenalectomized rat. On the basis of the above results it is speculated that the toxic effect of copper to hepatocytes is influenced not only by the concentration of the metal but by other factors, including adrenocortical hormones. An increased amount of adrenocortical hormones as a result of adrenocortical hyperfunction in copper treated rats may stabilize the lysosomes and protect the hepatic cell from the toxic effects of the metal.
[영문] Wilson's disease is one of the genetic disorders leading to the accumulation of excessive amount of copper, which in time causes pathologic changes in the patient's liver, brain, kidney, and cornea. Deficiency or absence of serum ceruloplasmin and elevated concentrations of hepatic copper are both characteristic and diagnostic abnormalities which precede the appearance of histopathologic hepatic changes(Goldfischer and Sternlieb, 1968). However, studies on the concentration of ceruloplasmin over the past two decades, have not provided a unified concept of all the abnormalities observed in this disease, although it provided an enormous amount of clinically useful data. And the mechanism by which copper exerts its toxic effect on the hepatic cells in Wilson's disease is unknown yet. Attempts to prodcue hepatic dysfunction and morphologic lesions equivalent to Wilson's disease in experimental animals have been unsuccessful. For example experimentally induced deposits of copper in hepatic cell generally do not produce necrosis (Howell, 1959; McNary, 1963; Barka, et al., 1964). Recently, results of many experiments on this subject suggested that sequestration of copper by lysosomes, may protect hepatocytes from toxic effects of the metal (Goldfischer and Moskal, 1966; Goldfischer, 1967; Goldfischer and Sternlieb, 1968; Goldfischer, et al., 1970). The present investigation was carried out to investigate wlether vitamin A administration and adrenalectomy, which are known to labilize and stabilize lysosomal membrane respectively, influence on copper toxicity in various organs, such as the liver, spleen and adrenal gland of the rat. Meterials and Methods Adult female albino rats were divided into five groups and treated as follows: Group Ⅰ: Normal control 16 rats Group Ⅱ: CuSo^^4 treated 16 rats Group Ⅲ: Vitamin A treated 16 rats Group Ⅳ: CuSo^^4 and vitamin A treated 20 rats Group Ⅴ: Adrenalectomy and CuSo^^4 treated 20 rats 0.3cc of 0.5% copper sulfate solution was given intraperitoneally per animal daily. Vitamin A was administered orally in a dose of 500 I.U. per gram of body weight daily. In group Ⅳ, animals were treated with copper sulfate for 5 days prior to combining treatment of copper sulfate and vitamin A. In group Ⅴ, a bilateral adrenalectomy was done and the animals were maintained with 1% saline solution. Copper sulfate treatment began 2 weeks after the adrenalectomy. At 3rd, 7th, 10th and 15th days, 4∼5 rats were killed by exanguination. Speciments for light microscopic studies were fixed in 10% neutral formalin and embedded in paraffin. Sections, 6 micron thick, were made and stained with hematoxylin and eosin routinely. Additionally, sodium diethyldithiocarbamate stain (Howell, 1959), oil red O stain, periodic acid Schiff reaction after diastase treatment, Gomori's iron reaction with the liver sections, Gomori's iorn reaction with the spleen sections, and oil red O stain with the adrenal sections were performed. Specimens for electron microscopic studies were obtained from the liver only. The specimens were cut in 1mm**3 in size and fixed in 1% osmic acid in phosphate buffer at pH 7.4, and embedded in Epon 812. After staining with uranyl acetate and lead hydroxide, an observation was made with a Hitachi HY 11-E model electron microscope. Result and Summary The results may be summerized as follows: 1) Neither marked necrosis, nor cirrhotic change of the liver was induced with copper sulfate only. But in the adrenal gland, increase in size and hyperplastic changes of zona fasciculats and zona reticularis were observed with an increased amount of fatty substances. 2) Large amounts of vitamin A administration induced inflammatory and necrotic changes in the liver. However, previous and combined treatment with copper sulfate could prevent this toxic effect of vitamin A on the liver. 3) Copper sulfate treatment to the adrenalectomized rat induced focal necrosis and an increase in hepatic cell mitoses which was very similar to the regenerative changes, and the copper accumulation was sightly accentuated compared to non-adrenalectomized rat. On the basis of the above results it is speculated that the toxic effect of copper to hepatocytes is influenced not only by the concentration of the metal but by other factors, including adrenocortical hormones. An increased amount of adrenocortical hormones as a result of adrenocortical hyperfunction in copper treated rats may stabilize the lysosomes and protect the hepatic cell from the toxic effects of the metal.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/117275
Appears in Collections:
2. 학위논문 > 1. College of Medicine (의과대학) > 박사
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