關木通

出自台灣有毒中草藥毒性資料庫

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== '''參考文獻''' ==
== '''參考文獻''' ==
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1. Santos AF, Argolo AC, Coelho LC, Paiva PM. Detection of water soluble lectin and antioxidant component from Moringa oleifera seeds. Water Res 2005; 39: 975-980.
+
1. Vanherweghem JL, Depierreux M, Tielemans C et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341: 387-391.
-
2. Eilert U, Wolters B, Nahrstedt A. The antibiotic principle of seeds of Moringa oleifera and Moringa stenopetala. Planta Med 1981; 42: 55-61.
+
2. 陳能照, 呂理哲. 龍膽瀉肝湯致末期腎衰竭-病例報告. 台灣家醫誌 2003; 13: 138-143.
-
3. Faizi S, Siddiqui BS, Saleem R et al. Isolation and structure elucidation of a novel glycoside niazidin from the pods of Moringa oleifera. Journal of Natural Products 1997; 60: 1317-1321.
+
3. 行政院衛生署食品藥物管理局 http://www.doh.gov.tw.  
-
4. Murakami A, Kitazono Y, Jiwajinda S et al. Niaziminin, a thiocarbamate from the leaves of Moringa oleifera, holds a strict structural requirement for inhibition of tumor-promoter-induced Epstein-Barr virus activation. Planta Med 1998; 64: 319-323.
+
4. Chen CH, Dickman KG, Moriya M et al. Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci U S A 2012; 109: 8241-8246.
-
5. Sahakitpichan P, Mahidol C, Disadee W et al. Unusual glycosides of pyrrole alkaloid and 4′-hydroxyphenylethanamide from leaves of Moringa oleifera. Phytochemistry 2011; 72: 791-795.
+
5. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monogr Eval Carcinog Risks Hum 2002; 82: 1-556.
-
6. Bijina B, Chellappan S, Basheer SM et al. Protease inhibitor from Moringa oleifera leaves: Isolation, purification, and characterization. Process Biochemistry 2011; 46: 2291-2300.
+
6. 謝宗萬. 全國中草藥匯編 上冊 第二版. 北京: 人民衛生出版社 1996. p.p. 339.
-
7. Shanker K, Gupta MM, Srivastava SK et al. Determination of bioactive nitrile glycoside(s) in drumstick (Moringa oleifera) by reverse phase HPLC. Food Chemistry 2007; 105: 376-382.
+
7. Rucker G, Mayer R, Wiedenfeld H et al. (+)-Isobicyclogermacrenal from Aristolochia-Manshuriensis. Phytochemistry 1987; 26: 1529-1530.
-
8. CSIR ND. Nitrile glycoside useful as a bioenhancer of drugs and nutrients, process of its isolation from Moringa oleifera. Patent 2005; 6: 588.
+
8. Chung YM, Chang FR, Tseng TF et al. A novel alkaloid, aristopyridinone A and anti-inflammatory phenanthrenes isolated from Aristolochia manshuriensis. Bioorganic & medicinal chemistry letters 2011; 21: 1792-1794.
-
9. Verma AR, Vijayakumar M, Mathela CS, Rao CV. In vitro and in vivo antioxidant properties of different fractions of Moringa oleifera leaves. Food Chem Toxicol 2009; 47: 2196-2201.
+
9. Nakanishi T, Iwasaki K, Nasu M et al. Aristoloside, an Aristolochic Acid-Derivative from Stems of Aristolochia-Manshuriensis. Phytochemistry 1982; 21: 1759-1762.
-
10. Villasenor IM, Lim-Sylianco CY, Dayrit F. Mutagens from roasted seeds of Moringa oleifera. Mutat Res 1989; 224: 209-212.
+
10. Wu PL, Su GC, Wu TS. Constituents from the stems of Aristolochia manshuriensis. Journal of natural products 2003; 66: 996-998.
-
11. Luqman S, Srivastava S, Kumar R et al. Experimental Assessment of Moringa oleifera Leaf and Fruit for Its Antistress, Antioxidant, and Scavenging Potential Using In Vitro and In Vivo Assays. Evid Based Complement Alternat Med 2012; 2012: 519084.
+
11. Chan W, Hui KM, Poon WT et al. Differentiation of herbs linked to "Chinese herb nephropathy" from the liquid chromatographic determination of aristolochic acids. Analytica Chimica Acta 2006; 576: 112-116.
-
12. Ghasi S, Nwobodo E, Ofili JO. Hypocholesterolemic effects of crude extract of leaf of Moringa oleifera Lam in high-fat diet fed wistar rats. J Ethnopharmacol 2000; 69: 21-25.
+
12. Rucker G, Ming CW, Mayer R et al. Manshurolide, a Sesquiterpene Lactone from Aristolochia-Manshuriensis. Phytochemistry 1990; 29: 983-985.
-
13. Gupta A, Gautam MK, Singh RK et al. Immunomodulatory effect of Moringa oleifera Lam. extract on cyclophosphamide induced toxicity in mice. Indian J Exp Biol 2010; 48: 1157-1160.
+
13. Hegde VR, Borges S, Patel M et al. New potential antitumor compounds from the plant Aristolochia manshuriensis as inhibitors of the CDK2 enzyme. Bioorganic & medicinal chemistry letters 2010; 20: 1344-1346.
-
14. Mahajan SG, Mehta AA. Immunosuppressive activity of ethanolic extract of seeds of Moringa oleifera Lam. in experimental immune inflammation. J Ethnopharmacol 2010; 130: 183-186.
+
14. Zeng Y, Yang X, Wang J et al. Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells. PLoS One 2012; 7: e30312.
-
15. 林燕明. 服辣木籽急性肝衰竭. In. 蘋果日報 2004.
+
15. Cui M, Liu ZH, Qiu Q et al. Tumour induction in rats following exposure to short-term high dose aristolochic acid I. Mutagenesis 2005; 20: 45-49.
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16. Awodele O, Oreagba IA, Odoma S et al. Toxicological evaluation of the aqueous leaf extract of Moringa oleifera Lam. (Moringaceae). Journal of Ethnopharmacology 2012; 139: 330-336.
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16. Xing G, Qi X, Chen M et al. Comparison of the mutagenicity of aristolochic acid I and aristolochic acid II in the gpt delta transgenic mouse kidney. Mutat Res 2012; 743: 52-58.
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17. Kavitha C, Ramesh M, Kumaran SS, Lakshmi SA. Toxicity of Moringa oleifera seed extract on some hematological and biochemical profiles in a freshwater fish, Cyprinus carpio. Experimental and toxicologic pathology 2011.
+
17. Priestap HA, Torres MC, Rieger RA et al. Aristolochic acid I metabolism in the isolated perfused rat kidney. Chem Res Toxicol 2012; 25: 130-139.
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18. Asare GA, Gyan B, Bugyei K et al. Toxicity potentials of the nutraceutical Moringa oleifera at supra-supplementation levels. Journal of Ethnopharmacology 2012; 139: 265-272.
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18. Stiborova M, Mareis J, Frei E et al. The human carcinogen aristolochic acid i is activated to form DNA adducts by human NAD(P)H:quinone oxidoreductase without the contribution of acetyltransferases or sulfotransferases. Environ Mol Mutagen 2011; 52: 448-459.
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19. Krishnaraju AV, Sundararaju D, Srinivas P et al. Safety and toxicological evaluation of a novel anti-obesity formulation LI85008F in animals. Toxicol Mech Methods 2010; 20: 59-68.
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19. Hu SL, Zhang HQ, Chan K, Mei QX. Studies on the toxicity of Aristolochia manshuriensis (Guanmuton). Toxicology 2004; 198: 195-201.
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20. Mazumder UK, Gupta M, Chakrabarti S, Pal D. Evaluation of hematological and hepatorenal functions of methanolic extract of Moringa oleifera Lam. root treated mice. Indian J Exp Biol 1999; 37: 612-614.
+
20. Xue X, Xiao Y, Gong L et al. Comparative 28-day repeated oral toxicity of Longdan Xieganwan, Akebia trifoliate (Thunb.) koidz., Akebia quinata (Thunb.) Decne. and Caulis aristolochiae manshuriensis in mice. Journal of Ethnopharmacology 2008; 119: 87-93.
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21. Rolim LA, Macedo MF, Sisenando HA et al. Genotoxicity evaluation of Moringa oleifera seed extract and lectin. J Food Sci 2011; 76: T53-58.
+
21. Working Party on Herbal Medicinal Products: Position paper on the risks associated with the use of herbal products containing Aristolochia species (EMEA/HMPWP/23/00). London: European Agency for the Evaluation of Medicinal Products. 2000.
 +
22. Liu MC, Maruyama S, Mizuno M et al. The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids. Clin Exp Nephrol 2003; 7: 186-194.
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23. Wen YJ, Qu L, Li XM. Ischemic injury underlies the pathogenesis of aristolochic acid-induced acute kidney injury. Transl Res 2008; 152: 38-46.
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24. Zhu S, Wang Y, Jin J et al. Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells. Toxicol In Vitro 2012.
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基本資料

科別

馬兜鈴科Aristolochiaceae

屬名

馬兜鈴屬 Aristolochia

中文學名

關木通

拉丁學名

Aristolochia mandshuriensis Kom.

英文名稱

Guanmutong, Caulis Aristolochiae Manshuriensis

中文俗名

馬木通、萬年藤、淮木通，木通馬兜鈴，東北木通


植物圖片

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關木通簡介

關木通主要為大陸產的東北馬兜鈴藤莖乾燥物。1993年，比利時一位醫師Vanherweghem發現數位婦女服用一種含有馬兜鈴酸成分的中草藥減肥藥後，出現快速進行性纖維化間質性腎炎的症狀，經檢驗才發現馬兜鈴酸為引起此症狀的最主要物質[1]，後續的研究也發現馬兜鈴酸具有致突變性的作用。

台灣因馬兜鈴酸導致腎病變較為有名的例子為一中醫師長期服用含有馬兜鈴酸的龍膽瀉肝錠後，罹患尿毒症，導致終身洗腎[2]。因此在2003年11月2日，衛生署公告全面禁用含有馬兜鈴酸的數種中藥材(廣防己，青木香，關木通，馬兜鈴，天仙藤等)，以防止民眾誤食韓馬兜鈴酸的藥材[3]。

2012年美國國家科學院期刊也發表一項研究結果，內容指出台灣尿道癌與馬兜鈴酸之間的關聯性相當高[4]。

目前除了馬兜鈴屬的植物被證實含有馬兜鈴酸外，同科的細辛屬也被發現含有馬兜鈴酸，因此目前也被禁止使用。世界衛生組織(WHO)下隸屬的國際癌症研究中心(IARC)也在2002年發表一份有關馬兜鈴酸的毒性評估報告，將馬兜鈴酸列為1級致癌物質(group 1)[5]。


外觀簡述

莖

木質藤本，可長達10公尺，莖粗3-8公分，外皮呈暗灰色，斷面淺黃色，有放射狀紋路及細小孔洞。

葉

葉互生，葉柄長，葉片呈圓心形，長約8-29公分，葉全緣或微波浪狀，嫩葉密生白色短柔毛，葉背藍白色，密生短毛。

花

夏季開花，單花腋生，花梗稍彎曲，有圓心型苞片1片，花被管向上見漸膨大，外表淡黃綠色，具紫色條紋，內面呈褐色或黃綠色，頂端處內曲如煙斗狀，頂端3裂，裂片寬卵圓形。雄蕊6柱，與柱頭貼生，子房下位細長，先端稍膨脹。

果實

蒴果圓柱狀，有6稜角，成熟時裂成六瓣，種子三角形，呈淡灰褐色。


產地

主產於中國東北各省，山西，陝西，甘肅亦有分佈。


使用情況

單方用於治療膀胱炎，尿痛，水腫，小便不利，乳汁不通，口舌生瘡。復方用於治療尿痛，口舌生瘡，肝硬化腹水，心性或腎性水腫[6]。


活性成份

莖[6-13]

  • 1. ( + )-isobicyclogermacrenal
  • 2. aristopyridinone A
  • 3. phenanthrenes (aristolamide II, aristolamide, aristolochic acid I, aristolochic acid-Iva, aristolochic acid-IIIa, aristolatams IIIa, aristolochic acid-I methyl ester, aristolic acid methyl ester, 6-methoxyaristolic acid methyl ester, aristolochic acid II
  • 4. Aristoloside
  • 5. demethylaristofolin E
  • 6. aristomanoside
  • 7. dehydrooxoperezinone
  • 8. manshurolide
  • 9. SCH 546909
  • 10. Magnoflorine
  • 11. Hederagenin
  • 12. Oleanolic acid


活性研究

  • 1. 低劑量(10 μM)，短時間內(3-6小時)給予aristolochic acid I，autphagy相關表現蛋白質LC3-II及Beclin 1表現量上升，並且在處理12小時後，仍無偵測到明顯的細胞凋亡現象。Aristolochic acid I也可在低劑量時透過ERK 1/2的路徑引起autophagy而減低細胞凋亡的產生，進而保護aristolochic acid I產生的腎臟組織傷害[14]。


毒性研究

  • 症狀
    • 1. 快速性纖維化間質性腎炎
    • 2. 急性腎衰竭
    • 3. 血壓稍微偏高
    • 4. 貧血
    • 5. 輕微蛋白尿輕微蛋白尿
    • 6. 腎臟萎縮
    • 7. 腎絲球缺血性變化

  • 有毒成分
    • 1. aristolochic acid I[15, 16]
    • 2. aristolochic acid II[16]

  • 中毒劑量
    • 1. SD大鼠 LD50: 29.2±3.71 g/kg[19]
    • 2. C57BL/6小鼠 NOAEL: 0.06 g/kg/day[20]
    • 3. 致癌劑量：

Aristolochic acid (AA I & AA II)

  • Oral
0.1 – 10 mg/kg, 3 days – 12 month
  • s.c.
1- 10 mg/kg, 35 days
  • i.p.
0.1 mg/kg, 17-21 month, rabbit
Extracts (decoction):
  • Oral
0.07 - 50 g/kg, 3-14 month 
**4. LD50[21]:

male

rat

oral 203.4 mg/kg
IV 82.5 mg/kg

mice

oral 55.9 mg/kg
IV 38.5 mg/kg

rabbit

i.v. 1-5 mg/kg

female

rat oral 183.9 mg/kg
i.v. 74.0 mg/kg
mice oral 106.1 mg/kg
i.v. 70.1 mg/kg

<>

  • 機轉
    • 1. aaritolochic acid經由口腔食入體內後，透過腎臟的周邊毛細管及腎小管快速且大量的進入腎臟組織，此時可藉由CYP1A1/2，quinone oxidoreductase，sulfotranferase及glucuronidation的代謝作用，將aritolochic acid代謝成aristolochic acid Ia O-sulfate，aristolactam Ia O-glucuronide，aristolochic acid Ia，aristolactam Ia O-sulfate，aristolactam Ia及aristolactam I等代謝物，而其中aristolochic acid Ia為最主要的代謝物（約佔總劑量的14.3%）[17]。
    • 2. aAristolochic acid I和II在經由腎臟代謝之後，代謝物與DNA形成的adduts主要有四種，分別為7-(deoxyadenosin-N6- yl) aristolactam I (dA-AAI), 7-(deoxyguanosin-N2-yl) aristolactam I (dG-AAI), 7-(deoxyadenosin-N6-yl) aristolactam II (dA-AAII) and 7-(deoxyguanosin-N2-yl) aristolactam II (dG-AAII)。其中aristolochic acid II所形成的adducts數量又比aristolochic acid I的量多上約2.5倍之多，由II形成的adducts引起的DNA突變頻率也相較I高出2倍之多。Aristolochic acid I及II形成的adducts造成的突變以A->T為最主要的突變形式，影響的基因為gpt gene[16]。
    • 3. 馬兜鈴酸在人體或動物體內為[5, 18]：

吸收

腸胃道吸收(gastrointenstinal tract)
分佈 以代謝或未代謝形式分佈
代謝

a. nitroreduction, O-methylation, denitration, N- and O-glucuronides, acetate and sulfate esters (in rats and mice) b. NAD(P)H:quinone oxidoreductase (in human) c. aristolactam I and II (in human urine)

排除 尿液

  • 腎臟毒性
    • 1. 北馬兜鈴根部水萃物，4 g/day給予Wistar母鼠連續五天，第五天時出現腎小管壞死(tubular necrosis)，氮質血症(azotemia)，尿蛋白(proteinuria)及糖尿(glucosuria)，在第14天時，有60%老鼠死於急性腎衰竭（萃取物含4 mgaristolochic acid），而直接給予4 mg/day aristolochic acid則只有20%死於急性腎衰竭，所有給藥的大鼠最後都出現腎小管損傷，腎功能降低，尿蛋白量上升。檢測大鼠臟器所含的aristolochic acid含量，由高至低分別為肺>腎>心>肝>脾。另，腎細胞增生現象在腎臟皮質及內外部隨質都可發現[22]。
    • 2. 大鼠口服北馬兜鈴萃取物（含20 mg/kg的aristolochic acid I），經組織病理切片發現腎臟出現急性局部缺血腎損傷(acute hypoxia renal injury)，同時也影響腎臟皮質的hypoxia inducible factor 1 alpha (HIF-1a)的mRNA表現量以及endothelin-1，血液肌肝酸(creatinine)量提高[23]。
    • 3. 以C57BL/6小鼠進行實驗，口服給予北馬兜鈴莖萃取物，28天後明顯觀察到小鼠血液中的ALT，BUN，CRE有顯著的增加(1.20 g/kg/day組)，而肝臟，脾臟及胸腺重量顯著的下降。腎臟病理組織切片也觀察到腎小管有明顯的擴張現象[20]。

  • 細胞毒性
    • 1. 直接給予HK-2細胞株(腎小管上皮細胞)100 μM的aristolochic acid I，發現內質網所媒介的細胞死亡現象明顯的表現，如磷酸化的eukaryotic initiation factor-2a (eIF2a), X-box binding protein 1 (XBP1) mRNA splicing及glucose-regulated protein (GRP) 78和CAAT/ enhancer-binding protein-homologous protein (CHOP)的表現量均有顯著的上升。另外，也間接証實ROS的含量有上升，推測可能是ROS引起endoplasmic reticulum stress[24]。

  • 致癌
    • 1. Aristolochic acid I由東北馬兜鈴中萃取，每日50 mg/kg/day餵食Sprague-Dawley母鼠，連續三天。8天後，母鼠血中尿素(urea)，肌肝酸(creatinine)，總尿量(urinary)及N-acetyl-β-glucosaminidase呈現顯著升高，而1個月，3個月及6個月後，均回復到正常值。另外，觀察給藥6個月後的組別，全數老鼠的腎臟都出現局部或擴散性的腫瘤發生前的增生現象(renal preneoplastic proliferation)，28.6%的老鼠出現腫瘤。由腎臟組織切片也可觀察到明顯的腫瘤及增生狀況[15]。


毒性分級

級數A, 等級3


參考文獻

1. Vanherweghem JL, Depierreux M, Tielemans C et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341: 387-391.

2. 陳能照, 呂理哲. 龍膽瀉肝湯致末期腎衰竭-病例報告. 台灣家醫誌 2003; 13: 138-143.

3. 行政院衛生署食品藥物管理局 http://www.doh.gov.tw.

4. Chen CH, Dickman KG, Moriya M et al. Aristolochic acid-associated urothelial cancer in Taiwan. Proc Natl Acad Sci U S A 2012; 109: 8241-8246.

5. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monogr Eval Carcinog Risks Hum 2002; 82: 1-556.

6. 謝宗萬. 全國中草藥匯編 上冊 第二版. 北京: 人民衛生出版社 1996. p.p. 339.

7. Rucker G, Mayer R, Wiedenfeld H et al. (+)-Isobicyclogermacrenal from Aristolochia-Manshuriensis. Phytochemistry 1987; 26: 1529-1530.

8. Chung YM, Chang FR, Tseng TF et al. A novel alkaloid, aristopyridinone A and anti-inflammatory phenanthrenes isolated from Aristolochia manshuriensis. Bioorganic & medicinal chemistry letters 2011; 21: 1792-1794.

9. Nakanishi T, Iwasaki K, Nasu M et al. Aristoloside, an Aristolochic Acid-Derivative from Stems of Aristolochia-Manshuriensis. Phytochemistry 1982; 21: 1759-1762.

10. Wu PL, Su GC, Wu TS. Constituents from the stems of Aristolochia manshuriensis. Journal of natural products 2003; 66: 996-998.

11. Chan W, Hui KM, Poon WT et al. Differentiation of herbs linked to "Chinese herb nephropathy" from the liquid chromatographic determination of aristolochic acids. Analytica Chimica Acta 2006; 576: 112-116.

12. Rucker G, Ming CW, Mayer R et al. Manshurolide, a Sesquiterpene Lactone from Aristolochia-Manshuriensis. Phytochemistry 1990; 29: 983-985.

13. Hegde VR, Borges S, Patel M et al. New potential antitumor compounds from the plant Aristolochia manshuriensis as inhibitors of the CDK2 enzyme. Bioorganic & medicinal chemistry letters 2010; 20: 1344-1346.

14. Zeng Y, Yang X, Wang J et al. Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells. PLoS One 2012; 7: e30312.

15. Cui M, Liu ZH, Qiu Q et al. Tumour induction in rats following exposure to short-term high dose aristolochic acid I. Mutagenesis 2005; 20: 45-49.

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