Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells
Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells
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DOI：
10.1111/j.1523-1755.2005.00277.x
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发表时间：
2005-05-01
影响因子：
19.6
通讯作者：
Pasco, DS
中科院分区：
文献类型：
--
作者：
Balachandran, P;Wei, F;Pasco, DS
背景马兜铃属植物具有肾毒性和致癌性。近年来的研究表明，马兜铃酸（aristolochic acid，AA）可引起多种动物的急性肾功能衰竭和肾小管损伤，并证实了AA在中药肾病中的作用。从马兜铃属植物中分离得到一系列AA衍生物。在LLC-PK 1细胞培养物中使用中性红染料排除试验分析其肾毒性潜力。AA I及其类似物之间的结构关系进行了比较，其细胞毒性作用预测AA毒性的结构决定因素。此外，对有毒化合物进行了半胱天冬酶-3测定，以确定半胱天冬酶（在细胞凋亡中发挥关键作用的酶）是否参与AA诱导的细胞毒性。结果。AA I被认为是最有毒的，其次是AA II，AA VIIIa和AA 1a的毒性水平降低。其他化合物，硝基菲羧酸类似物的AA I，马兜铃内酰胺，和其他衍生物没有表现出相当大的毒性。结果表明，AA化合物的细胞毒性与其结构中官能团的位置有明显的关系。含有羟基的类似物降低了细胞毒性。AA I的去甲基化类似物的活性明显降低。AA I的硝基还原对细胞毒性有负面影响。AA诱导的caspase活化也被抑制。这些细胞毒性数据表明，硝基和甲氧基是AA的肾毒性效力的关键决定因素。
Background. Aristolochia species are nephrotoxic and carcinogenic. Recent studies showed that aristolochic acid (AA) could induce acute renal failure and tubular lesions in several species and available evidences demonstrate the unequivocal role of AA in so called Chinese herbs nephropathy.Methods. A series of AA derivatives isolated from Aristolochia spp. were analyzed for their nephrotoxic potential using the neutral red dye exclusion assay in cultures of LLC-PK1 cells. The structural relationships between AA I and its analogues were compared with their cytotoxic effects to predict structural determinants for AA toxicity. Further, caspase-3 assay was performed on toxic compounds to determine if caspases, the enzymes that play a critical role in apoptosis are involved in AA-induced cytotoxicity.Results. AA I was found to be most toxic followed by AA II, AA VIIIa, and AA la in decreasing levels of toxicity. The other compounds, nitrophenanthrene carboxylic acid analogues of AA I, aristolactams, and other derivatives did not exhibit considerable toxicity. The results showed significant relationships between cytotoxicity of AA compounds and the localization of functional groups in their structure. Analogues containing hydroxyl groups diminished cytotoxicity. The demethylated analogues of AA I are markedly less active. The negative impact on cytotoxicity was found on nitroreduction of AA I. AA induced caspase activation was also observed.Conclusion. These cytotoxic data suggest that the nitro and methoxy groups are critical determinants of nephrotoxicologic potency of AA.