本文選題：急性毒性 + 亞慢性毒性��； 參考：《南京農(nóng)業(yè)大學(xué)》2015年碩士論文

【摘要】：胰蛋白酶(Trypsin)是最早發(fā)現(xiàn)于胰液消化蛋白質(zhì)中的酶。胰蛋白酶在脊椎動(dòng)物消化系統(tǒng)中是一種重要的消化酶,其在胰臟中先以胰蛋白酶原的形式而被合成,然后隨胰液從胰島管進(jìn)入小腸,在小腸內(nèi)經(jīng)腸激酶激活后活化為胰蛋白酶。胰蛋白酶能特異性的切斷多肽鏈中賴氨酸和精氨酸殘基的羧基側(cè)。胰蛋白酶還能激活其他一些酶的前體,例如羧肽酶原、糜蛋白酶原等,是一種特異性非常強(qiáng)的蛋白酶。胰蛋白酶作為一種蛋白水解酶,能降解變性的蛋白質(zhì),對(duì)未變性的蛋白質(zhì)則不起作用。因此,胰蛋白酶能分解膿液、血凝塊等,利于膿液的引流排除,從而使壞死創(chuàng)面凈化速度加快,并能促進(jìn)肉芽組織的新生。在人醫(yī)臨床上主要用于膿胸、血胸、瘺管等所產(chǎn)生的局部水腫、膿腫的治療,也用于毒蛇咬傷治療;在生物科技上常用于細(xì)胞培養(yǎng)。目前關(guān)于胰蛋白酶在獸醫(yī)臨床上的應(yīng)用報(bào)道鮮見,胰蛋白酶尚未作為獸用藥物在國內(nèi)進(jìn)行注冊。依照農(nóng)業(yè)部獸藥評(píng)審中心獸藥注冊資料匯編的毒理學(xué)試驗(yàn)規(guī)定,本研究對(duì)胰蛋白酶原料藥進(jìn)行了包括小鼠急性毒性試驗(yàn)、大鼠30天喂養(yǎng)亞慢性毒性試驗(yàn)、小鼠骨髓細(xì)胞微核試驗(yàn),以及復(fù)合蛋白酶乳房注入劑在家兔的皮膚和黏膜刺激試驗(yàn)、皮膚致敏試驗(yàn)在內(nèi)的一般毒理學(xué)試驗(yàn)研究。給小鼠灌服劑量分別為 40 mg/kg,200 mg/kg,1000 mg/kg,5000 mg/kg 和8000 mg/kg的胰蛋白酶原料藥進(jìn)行急性毒性試驗(yàn),結(jié)果顯示,胰蛋白酶的LD505000 mg/kg,根據(jù)化學(xué)物質(zhì)急性毒性劑量分級(jí)表判定胰蛋白酶原料藥屬于實(shí)際無毒物質(zhì);給大鼠灌服為期30 d的劑量分別為高劑量(800 mg/kg)、中劑量(400mg/kg)、低劑量(200mg/kg)的胰蛋白酶原料藥進(jìn)行亞慢性毒性試驗(yàn),試驗(yàn)結(jié)果顯示,各個(gè)劑量組的大鼠均未出現(xiàn)明顯中毒情況,受試大鼠的血液常規(guī)、血液生化指標(biāo)中盡管有個(gè)別指標(biāo)與對(duì)照組相比有顯著差異,但數(shù)值均處于正常范圍內(nèi),臟器系數(shù)指標(biāo)與對(duì)照組均無顯著差異,病理組織學(xué)檢查也未見異常。將復(fù)合蛋白酶乳房注入劑涂在家兔背部完整皮膚,觀察其對(duì)皮膚的刺激和致敏情況;同時(shí)將復(fù)合蛋白酶乳房注入劑注入家兔陰道,觀察其對(duì)黏膜刺激性,試驗(yàn)結(jié)果顯示,復(fù)合蛋白酶乳房注入劑對(duì)家兔皮膚和陰道黏膜未產(chǎn)生明顯刺激性,同樣也未引起家兔皮膚的過敏反應(yīng);給小鼠灌服劑量分別為LD50(5000mg/kg)、1/2LD50(2500 mg/kg)、1/4 LD50(1250 mg/kg)的胰蛋白酶原料和陽性對(duì)照藥物環(huán)磷酰胺(40 mg/kg)及等量蒸餾水進(jìn)行小鼠骨髓細(xì)胞微核致突變試驗(yàn),結(jié)果顯示骨髓細(xì)胞微核致突變試驗(yàn)為陰性,表明胰蛋白酶原料對(duì)體細(xì)胞無致突變作用。
[Abstract]:Trypsin is the first enzyme found in pancreatic juice to digest proteins.Trypsin is an important digestive enzyme in the digestive system of vertebrates. Trypsin is synthesized in the form of trypsinogen in the pancreas, then enters the small intestine with the pancreatic fluid from the islet duct, and activates into trypsin after activation by enterokinase in the small intestine.Trypsin can specifically cut the carboxyl side of lysine and arginine residues in the polypeptide chain.Trypsin also activates precursors of other enzymes, such as carboxypeptidase, chymotrypsinogen, and is a highly specific protease.As a proteolytic enzyme, trypsin degrades denatured proteins, but does not act on undenatured proteins.Therefore, trypsin can decompose the pus, blood clot and so on, which is conducive to the drainage and exclusion of the pus, thus speeding up the purification of necrotic wounds and promoting the regeneration of granulation tissue.It is mainly used in the treatment of local edema and abscess caused by empyema, hemothorax, fistula and so on. It is also used in the treatment of venomous snake bite, and is often used in cell culture in biotechnology.At present, there are few reports on the application of trypsin in veterinary clinic. Trypsin has not been registered as a veterinary drug in China.In accordance with the provisions of toxicological tests compiled by the Veterinary Drug Evaluation Center of the Ministry of Agriculture, this study conducted acute toxicity tests on trypsin raw materials, including acute toxicity tests in mice, and subchronic toxicity tests on 30 days feeding rats.The micronucleus test of mouse bone marrow cells, the skin and mucous membrane irritation test of rabbits with complex protease breast implants, and the general toxicological test including skin sensitization test.Acute toxicity tests were conducted in mice at doses of 40 mg / kg ~ (200 mg / kg ~ (-1) mg / kg ~ (-1) mg 路kg ~ (-1) ~ (-1) mg 路kg ~ (-1)) of trypsin for 5000 mg/kg and 8000 mg/kg, respectively.The LD505000 mg / kg of trypsin, according to the acute toxic dose scale of the chemical substances, the trypsin raw material was classified as the actual nontoxic substance.The subchronic toxicity test of trypsin raw drug was carried out in rats at high doses of 800 mg / kg, middle dose of 400 mg / kg and low dose of 200 mg / kg of trypsin respectively for 30 days. The results showed that there was no obvious toxicity in each dose group.The blood routine and blood biochemical indexes of the tested rats were significantly different from those of the control group, but the values were within the normal range, and there was no significant difference between the viscera coefficient index and the control group.Histopathological examination was not abnormal.In order to observe the irritation and sensitization of the skin in the back of the rabbit, the compound protease breast injection agent was applied to the intact skin of the rabbit back to observe the irritation of the mucous membrane by injecting the compound protease breast injection agent into the vagina of the rabbit.There was no obvious irritation to rabbit skin and vagina mucosa after breast injection of complex protease, and no allergic reaction of rabbit skin was also caused.The micronucleus mutagenicity test of bone marrow cells in mice was carried out by injecting the trypsin raw material and positive control drug cyclophosphamide 40 mg / kg and distilled water at the dose of LD50 5000mg / kg 1 / 2LD50,500mg / kg 2500mg / kg respectively. The results showed that the micronucleus mutagenicity test of bone marrow cells was negative.The results showed that trypsin had no mutagenicity on somatic cells.
【學(xué)位授予單位】：南京農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：S859.7

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