台灣馬兜鈴酸的致癌性－－轉譯醫學之證據

The Translational Evidence of Aristolochic Acid-Related Carcinogenesis in Taiwan

癌症的發生具有多因性，許多環境因子都可能是致癌物。於1993年比利時婦女服用含有馬兜鈴酸成份的減肥藥引起急性腎衰竭之後，許多的研究指出馬兜鈴酸有可能引起不可逆的腎臟病以及泌尿道的癌症。上泌尿道泌尿上皮癌一般約占所有泌尿上皮癌5%-10%，然而在台灣上泌尿道上皮癌的發生率卻比世界發生率來的高，洗腎人口也較多，而洗腎病患又容易得到上泌尿道上皮癌，推測與台灣人習慣使用中草藥因此攝取了馬兜鈴酸有關。有關馬兜鈴酸的致癌機轉，研究顯示出馬兜鈴酸進入人體代謝成aristolactam'與DNA結合形成aristolactam-DNA adducts沉積在腎臟皮質與泌尿上皮中而引起突變而致癌。引起突變的形式以A：T to T：A transvesion為主，與一般上泌尿道上皮癌突變以G:C to AT 的transversion.不同。進一步經由全基因定序發現除了A：T to T：A transversion以外，在突變點的5'與3'端各有特定的序列，包含突變點的片段A［C｜T］□GG就成了馬兜鈴酸引起的突變特有的mutational signature。這個特別的突變指紋配合aristolactam-DNA adducts 可應用於偵測病人是否曾攝取過馬兜鈴酸，以及是否可能因此具有罹癌的風險。

The cause of cancer is multifactorial. Many environmental factors could be carcinogens. In 1993, women in Belgium were found to have taken diet medicine with the ingredient of aristolochic acid and developed renal failure, since then lots of studies provided evidence that aristolochic acid might induce nephropathy and urinary tract cancer. The upper tract urothelial carcinoma accounts for about 5-10% of urothelial cancer worldwide. However, the rate of upper tract urothelial carcinoma is much higher in Taiwan, especially in patients with end-stage renal disease and received maintenance hemodialysis. It is possible that the incident is related to the wide use of Chinese herbs containing aristolochic acid in Taiwan. After entering human body, the aristolochic acid would become aristolactam after metabolism and bind to DNA and form aristolactam-DNA adducts. The aristolactam-DNA adducts may deposit in renal cortex and urothelium to induce mutation, resulting in cancer development. Mutation related to aristolochic acid is mainly A:T to T:A transversion, instead of G:C to A:T transition, which is usually seen in upper tract urothelial carcinoma not related to aristolochic acid. The genome-wide sequencing revealed that aristolochic acid tends to mutate the DNA in a specific motif site with A[C|T]AGG sequence, and this specific motif can be the mutational signature of aristolochic acid. By combining the mutational signature and aristolactam-DNA adducts, we can use them as a screening tool to evaluate whether a patient has been exposed to aristolochic acid toxication, and assess the risk of cancer development.