臺灣博碩士論文加值系統

馬兜鈴科細辛屬植物「細辛」為常用藥，據研究報告指出其含有極微量致腎毒性的馬兜鈴酸，亦含有可能致肝毒性的黃樟醚，其複方製劑「獨活寄生湯」、「小青龍湯」臨床使用亦相當普遍。本研究目的在探討不同部位「細辛」和其複方「獨活寄生湯」與「小青龍湯」於小鼠體內之安全性評估。
首先研究對馬兜鈴酸之致腎毒性較敏感的小鼠品系，每日以馬兜鈴酸(2.5、5.0、或10.0 mg/kg)胃管餵食雄性ICR或C3H/He品系小鼠，連續餵食12天，觀察血液與尿液腎功能指標及病理組織切片，結果顯示C3H/He小鼠對馬兜鈴酸之致腎毒性較ICR小鼠更為敏感。接著探討細辛和「獨活寄生湯」於小鼠之安全性評估，以雄性C3H/He鼠(約7~9週齡)，每日以胃管餵食馬兜鈴酸(3 mg/kg)、黃樟醚(300 mg/kg)、細辛根部浸膏(低、中、高劑量，分別為臨床常用劑量之30、90、300倍)、與獨活寄生湯浸膏(低、高劑量，分別為臨床常用劑量之10、30倍)共28天後，翌日犧牲解剖；以代謝籠收集尿液以分析尿液生化指標（Total urinary protein、Creatinine）、採心臟血分析血液生化指標（Blood urine nitrogen、Plasma creatinine、GOT、GPT）、採固定組織觀察切片之組織學變化、與以腎小管損傷相關指標中性內胜肽酶（neutral endopeptidase，NEP）進行免疫組織染色等，來探討細辛與獨活寄生湯於成鼠之安全性評估。結果顯示與正常對照組相較，除了馬兜鈴酸組及細辛高劑量組體重有減輕現象，其他各組體重與臟器重則無顯著變化。除馬兜鈴酸組與黃樟醚組外，其他組別的尿液及血液生化指標皆無顯著差異。觀察腎組織切片，馬兜鈴酸組的腎小管大量壞死，細辛浸膏高劑量組僅輕微的發炎細胞浸潤，其餘組別均屬正常；觀察肝組織切片，發現馬兜鈴酸組及黃樟醚組於門脈區有壞死現象，其餘組別相較於正常對照組則未有顯著差異。觀察NEP在腎組織的表現，僅馬兜鈴酸及細辛浸膏高劑量組，具有統計上顯著性的降低。
進一步探討不同部位的細辛與幼兒常用方劑「小青龍湯」之安全性評估，每日以胃管餵食雄性C3H/He幼鼠(約4~5週齡)細辛根部或全草浸膏（低、高劑量，分別為臨床常用劑量之18、180倍）、廣防己浸膏（1.5 g生藥/kg）、小青龍湯浸膏（為臨床常用劑量之39倍）共14天後，翌日犧牲解剖。結果顯示僅廣防己組的小鼠其腎臟重量變化具有顯著差異，廣防己組與細辛全草及根部之高劑量組會顯著提高尿蛋白與BUN的量。但只有廣防己組與細辛全草之高劑量組會顯著提高GOT與GPT值，並且於腎組織切片發現有輕微的發炎細胞浸潤現象，於肝組織切片發現有門脈區有空泡變性，而細辛根部之高劑量組則未有顯著差異。觀察NEP在腎組織的表現，僅廣防己組具有統計上顯著降低。
結果提供不同部位細辛、獨活寄生湯與小青龍湯的毒性物質相關資料，小鼠連續28天給「獨活寄生湯」至15.5 g生藥/kg (約為臨床常用劑量之30倍)，於各項安全性評估觀察指標中，未發現有顯著變化或有不良影響。同樣條件下，「細辛根部」組小鼠的無明顯不良效應的最高劑量（No observed adverse effect level, NOAEL）為5.0 g生藥/kg/day (約為臨床常用劑量之90倍)。幼鼠連續14天給「小青龍湯」17.6 g生藥/kg/day (約為臨床常用劑量之39倍)、或細辛根部或全草1 g生藥/kg/day (約為臨床常用劑量之18倍)，並未觀察到有不良反應。綜合以上動物實驗結果，根部「細辛」在臨床常用劑量下使用28天應是安全的。目前臨床上細辛皆用其根部且多配伍使用，細辛複方「獨活寄生湯」、「小青龍湯」在一般臨床劑量下使用14天應是安全的，此研究結果可提供作為臨床用藥之參考。

Aristolochic acid (AA), a probable human carcinogen, is found in Aristolochia fangchi that causes urothelial carcinomas in patients with Aristolochic acid Nephropathy. Xixin contains not only very small amounts of AA but also the hepatotoxic compound, safrole. Du Huo Ji Sheng Tang and Xiao Qing Long Tang are two of Xixin-containing formula commonly used in Chinese medicine. It is conceivable that the ingredients in the herbal formula traditionally used by the Chinese medical doctor could either enhance or decrease the potential toxicity of Xixin. In the study, an established C3H/He mouse model that exhibits enhanced susceptibility to AA-induced nephrotoxicity was used to assess the safety of Xixin and its formulas (Du Huo Ji Sheng Tang and Xiao Qing Long Tang).
In a 28-d feeding toxicity test, male C3H/He mice（about 7∼9 week old）were administered by gavage with Xixin (roots) at the doses of 30, 90 and 300 times of the clinical dose and Du Huo Ji Sheng Tang at the doses of 10 and 30 times of the clinical dose for 28 days. Furthermore, in a 14-d feeding toxicity test, the young mice（about 4∼5 week old）were administered by gavage with different parts of Xixin (roots or whole plant) at the doses of 18 and 180 times of the clinical dose, Xiao Qing Long Tang at the doses of 39 times of the clinical dose, and Aristolochia fangchi （1.5 g crude drug/kg）for 14 days. The potential renal and hepatic toxicity was examined to assess the safety of Xixin and its formulas. The parameters of renal and liver function（the level of urine creatinine, urine total protein, blood urea nitrogen, plasma creatinine, GOT, GPT）, the histopathological examination and immunohistochemistry staining（the renal tubular damage marker Neutral endopeptidase, NEP）of renal and liver tissue sections in exposed mice were examined.
During the first part of the experiment, the body weight of AA-treated and the high-dose of Xixin (roots)-treated mice were significantly reduced. After 4 weeks treatment, levels of urine total protein/creatinine, blood urea nitrogen, plasma creatinine in AA-treated group were significantly higher than those of control, but others were not affected. Safrole-treated group showed higher level of GPT and pathological evidence of liver toxicity. Histopathological examination provided evidence of proximal tubular necrosis in AA-treated group and slight tubule-interstitial injury in the high-dose Xixin（roots）-treated group, and both groups showed the decrease of the immunohistochemical expression of NEP in the proximal tubule brush border. In the group of Du Huo Ji Sheng Tang showed no signs of overt toxicity in all tests examined.
Moreover, in the second part of the experiment, after 2 weeks treatment in young mice, the Aristolochia fangchi-treated group and the high-dose group of Xixin （whole plant and roots） significantly increased the levels of urine total protein/creatinine and blood urea nitrogen. The levels of GOT and GPT as well as the pathological scores of tubular damage in the Aristolochia fangchi-treated group and the high-dose group of Xixin （whole plant） were significantly higher than those of control, whereas the high-dose group of Xixin（roots）were not. In the group of Xiao Qing Long Tang showed no signs of overt toxicity in all tests examined.
Our results demonstrated that the no observed adverse effect level （NOAEL) in mice following exposure to Xixin（roots）and Du Huo Ji Sheng Tang for 28 says were 5.0 g and 15.5 g crude drug/kg per day, respectively. The NOAEL of Xixin（whole plant or roots）and Xiao Qing Long Tang in young mice for 14 says were 1.0 g and 17.6 g crude drug/kg per day, respectively. These data may provide a better understanding on the safety of Xixin and its formula and provide some guidelines on how to use AA-containing herbs safely.

目錄

第一章、 前言...................................................................................... 1
第二章、 文獻探討.............................................................................. 2
第一節 中草藥腎病變之探討.......................................................... 2
壹. 馬兜鈴酸腎病起源.............................................................. 2
貳. 中草藥腎病變的病因及馬兜鈴酸...................................... 3
參. 馬兜鈴酸腎病變病理特徵.................................................. 4
肆. 馬兜鈴酸致癌機理.............................................................. 5
第二節 細辛的探討.......................................................................... 8
壹. 細辛的基源.......................................................................... 8
貳. 細辛的主要化學成分.......................................................... 8
參. 細辛的性味及歸經及主治.................................................. 9
肆. 細辛的現代藥理作用.......................................................... 9
伍. 臨床應用.............................................................................. 13
第三節 黃樟醚的毒性和致癌機轉.................................................. 14
壹. 黃樟醚的特性和致癌性...................................................... 14
貳. 含黃樟醚成分之植物種類.................................................. 15
參. 黃樟醚的肝毒性和體內代謝機理...................................... 15
第四節 中藥配伍理論和現代研究.................................................. 16
壹. 中藥配伍理論...................................................................... 16
ㄧ 配伍定義.............................................................................. 16
二 配伍用藥的方法和理論...................................................... 16
三 配伍之內容.......................................................................... 17
貳 中藥配伍作用的現代研究.................................................. 18
第五節 甘草的探討.......................................................................... 19
壹 甘草的基源.......................................................................... 19
貳 甘草的主要化學成分.......................................................... 19
參 甘草的性味及歸經及主治.................................................. 19
肆 甘草的解毒作用.................................................................. 20
伍 甘草的藥理作用.................................................................. 20
第六節 含細辛的方劑–《獨活寄生湯》之探討............................ 24
第七節 含細辛的方劑–《小青龍湯》之探討................................ 28
第三章、 實驗材料與方法.................................................................. 30
第一節 材料...................................................................................... 30
壹 實驗動物.............................................................................. 30
貳 實驗藥物製備...................................................................... 30
第二節 方法...................................................................................... 31
壹 實驗設計.............................................................................. 31
貳 尿液及血液收集.................................................................. 33
參 組織切片製作...................................................................... 34
肆 蘇木紫-伊紅染色法............................................................. 34
伍 組織免疫染色...................................................................... 34
陸 組織損傷程度的量化.......................................................... 35
柒 NEP的量化.......................................................................... 35
捌 統計方法.............................................................................. 36
第四章、 結果...................................................................................... 37
第五章、 討論...................................................................................... 76
第六章、 結論...................................................................................... 82
參考文獻.............................................................................. 83
英文摘要.............................................................................. 92

參考文獻

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