Yun Byeong Hwa, Sidorenko Viktoriya S, Rosenquist Thomas A, Dickman Kathleen G, Grollman Arthur P, Turesky Robert J
Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Toxicol Res (Camb). 2015 Jul 1;4(4):763-776. doi: 10.1039/C5TX00052A.
Aristolochic acids (AA) are found in all herbaceous plants, many of which have been used worldwide for medicinal purposes for centuries. AA are causal agents of the chronic kidney disease entity termed aristolochic acid nephropathy (AAN) and potent upper urinary tract carcinogens in humans. AAN and upper urinary tract cancers are endemic in rural areas of Croatia and other Balkan countries where exposure to AA occurs through the ingestion of home-baked bread contaminated with seeds. In Asia, exposure to AA occurs through usage of traditional Chinese medicinal herbs containing . Despite warnings from regulatory agencies, traditional Chinese herbs containing AA continue to be used world-wide. In this review, we highlight novel approaches to quantify exposure to AA, by analysis of aristolactam (AL) DNA adducts, employing ultraperformance liquid chromatography-electrospray ionization/multistage mass spectrometry (UPLC-ESI/MS). DNA adducts are a measure of internal exposure to AA and serve as an important end point for cross-species extrapolation of toxicity data and human risk assessment. The level of sensitivity of UPLC-ESI/MS surpasses the limits of detection of AL-DNA adducts obtained by P-postlabeling techniques, the most widely employed methods for detecting putative DNA adducts in humans. AL-DNA adducts can be measured by UPLC-ESI/MS, not only in fresh frozen renal tissue, but also in formalin-fixed, paraffin-embedded (FFPE) samples, an underutilized biospecimen for assessing chemical exposures, and in exfoliated urinary cells, a non-invasive approach. The frequent detection of AL DNA adducts in renal tissues, combined with the characteristic mutational spectrum induced by AA in and other genes provides compelling data for a role of AA in upper urothelial tract cancer.
马兜铃酸（AA）存在于所有草本植物中，其中许多植物在世界各地已被用于医疗目的达数百年之久。AA是被称为马兜铃酸肾病（AAN）的慢性肾病的致病因子，也是人类强效上尿路致癌物。AAN和上尿路癌症在克罗地亚农村地区及其他巴尔干国家流行，在这些地区，人们通过摄入被种子污染的自制面包接触到AA。在亚洲，人们通过使用含有AA的传统中草药接触到AA。尽管监管机构发出了警告，但含有AA的传统中草药仍在全球范围内使用。在本综述中，我们重点介绍了通过超高效液相色谱 - 电喷雾电离/多级质谱法（UPLC - ESI/MS）分析马兜铃内酰胺（AL）DNA加合物来量化AA暴露的新方法。DNA加合物是衡量AA体内暴露水平的指标，也是毒性数据跨物种外推和人类风险评估的重要终点。UPLC - ESI/MS的灵敏度超过了通过P - 后标记技术获得的AL - DNA加合物的检测限，P - 后标记技术是检测人类中推定DNA加合物最广泛使用的方法。AL - DNA加合物不仅可以通过UPLC - ESI/MS在新鲜冷冻肾组织中测量，还可以在福尔马林固定、石蜡包埋（FFPE）样本（一种未充分利用的用于评估化学暴露的生物样本）以及脱落尿细胞（一种非侵入性方法）中测量。肾组织中频繁检测到AL DNA加合物，再加上AA在某些基因和其他基因中诱导的特征性突变谱，为AA在上尿路上皮癌中的作用提供了令人信服的数据。
