利用細胞培養腎小管模式評估中藥安全性
陸德齡
中國醫藥大學藥學系
1990-1993年超過100個婦女服用中藥減肥後引起腎衰竭，而防己中馬兜鈴酸(aristolochic acid)是造成腎毒性的主要成分，也因此造成中藥材有肝腎毒性的疑慮，本計畫之重點欲已三度空間培養腎小管，以此介於動物與單純細胞培養之間的模式評估中藥材的安全性。已知馬兜鈴酸會與腎臟細胞中DNA結合，導致腎小管上皮細胞壞死，腎臟間質纖維化(interstitial fibrosis)，最後導致腎衰竭及尿道癌等不良反應。因此以馬兜鈴酸處理三度空間培養腎小管，我們發現馬兜鈴酸抑制腎小管之生成。因此可用此種模式，確認馬兜鈴酸造成之腎損傷。在1993年馬兜鈴酸事件中另一中藥為厚朴，然厚朴對腎毒性仍存有不同之看法，經文獻查詢厚朴中成分honokiol反而具有抑制腎臟發炎之作用，故本計畫將以honokiol、厚朴單方及含厚朴方劑處理三度空間培養腎小管，以釐清厚朴是保護或加成馬兜鈴酸引起之腎損傷。另外半夏中成分homogentisic acid是酪胺酸帶謝中間產物，若代謝酵素缺失的人服用homogentisic acid易造成腎毒性，產生憨色尿液，因此我們將以homogentisic acid、半夏單方含半夏方劑高劑量處理三度空間培養腎小管，以此模式評估其安全性。因為腎臟細胞間彼此間隙與腎小管發育有著密切關係，經由西方墨點法分析，可了解可能機轉，並初步評估中藥安全。
關鍵字：馬兜鈴酸；細辛；腎小管；中草藥
Evaluation the Chinese herb safety on cultured renal tube
Te-Ling Lu
School of Pharmacy, China Medical University, Taichung, Taiwan
Over 100 cases of kidney failure in Belgium were attributed to the herbal weight control regimen prescribed by the weight control clinic between 1990 and 1993. Aristolochic acid is the major factor to cause Chinese herb nephropathy. MDCK cells cultured in medium containing collagen become renal tubes. When cells were treated with aristolochic acid, the renal tubulogenesis is inhibited. Hence, we want to use this model to investigate the safety of Chinese herbs on renal tubulogenesis. Although aristolochic acidis is the major factor to cause nephropathy, some Chinese herbs can protect renal damage. Honokiol isolated from Magnolia officinalis attenuates renal fibrosis. These results prompt us to investigate the renal damage by honokiol, Magnolia officinalis or recipes containingMagnolia officinalis with aristolochic acid treatment. After this investigation, we can determine whether Magnolia officinalis is protective or synergistic on renal damage by aristolochic acid. On the other hand, alkaptonuria is an autosomal recessive disorder characterized by increased urinary excretion of homogentisic acid. Homogentisic acid is an intermediary component in the metabolism of tyrosine and phenylalanine. Accumulation of the homogentisic acid results from the enzyme deficiency that catabolize homogentisic acid. Homogentisic acid is one of the components of Pinellia ternate. We also use this model to evaluate the safety of homogentisic acid, Pinellia ternate, recipes containing Pinellia ternate on renal damage. Meanwhile, we also evaluate the mechanisms of Chinese herbs on renal tubulogenesis by western bolt analysis.
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