马兜铃酸（AA）是马兜铃酸肾病(aristolochic acid nephropathy, AAN) 和巴尔干地方性肾病(Balkan endemic nephropathy, BEN)的致病原因，已经引起了国际上的高度重视。氧化和还原是AAI（AA的主要毒性成分）在不同物种体内快速清除必不可少的代谢过程。然而，哪些酶参与AAI体内的氧化、还原代谢以及此代谢过程在AAI肾毒性中的作用尚不明确。
中科院上海药物研究所安评中心前期的研究工作表明，肝脏CYP1A参与AAI的氧化代谢，此代谢过程使小鼠血液及肾脏中AAI的含量降低继而减轻AAI所致的肾毒性。该研究结果已在Kidney Int(2008,73:1231-1239)杂志上发表。
肾脏不仅是还原代谢AAI能力最强的器官，也是AAI毒性的靶器官。因此，该中心在前期研究工作的基础上，进一步探索了哪种酶参与肾脏AAI的还原代谢以及此代谢过程对AAI肾毒性的影响。结果显示，NAD(P)H:醌氧化还原酶（NQO1）在肾脏具有较高的活性，且分布位置与AAI所致肾脏病变的部位一致。NQO1的抑制剂双香豆素、苯茚二酮均可抑制AAI在肾脏内的还原代谢，延缓AAI的血浆清除。虽然抑制剂处理后，小鼠血液和肾脏中AAI的含量明显升高，但其所致肾毒性却显著降低，表明NQO1参与AAI在肾脏内的还原代谢，且这一还原代谢过程可能是AAI诱发肾脏毒性的主要原因。
此部分研究结果最近发表在毒理学领域颇具影响力的杂志《毒理学》（Toxicol Sci） 上。该结果为深入研究AAN机理提供了新的依据，为马兜铃酸肾病预防提供了新的线索，同时也为中药安全性研究提供了新的思路。
生物探索推荐英文摘要
Inhibition of renal NQO1 activity by dicoumarol suppresses nitroreduction
of aristolochic acid I and attenuates its nephrotoxicity
Abstract： Aristolochic acid I (AAI) is the major toxic component of aristolochic acid (AA), which causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Nitroreduction is an essential metabolic process for AAI rapid clearance in different species including human. However, which enzyme participates in AAI nitroreduction in vivo and whether this metabolic process contributes to AAI nephrotoxicity are unclear. Here, we showed that NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in mouse renal tubular epithelial cells. Inhibition of NQO1 activity by dicoumarol pretreatment significantly decreased renal aristolactam I (ALI) levels, a major reductive metabolite of AAI, while increased renal AAI and its major oxidative metabolite 8-hydroxy-aristolochic acid I (AAIa) levels in male C57BL/6 mice. Similar changes in renal ALI, AAI and AAIa levels were also observed in mice pretreated with another NQO1 inhibitor, phenindione. Consistent with higher levels of renal AAI and AAIa found in dicoumarol-pretreated mice, their serum clearance was much slower compared with vehicle-pretreated mice. The survival rate of mice pretreated with dicoumarol was markedly increased when higher doses of AAI were given. Similarly, pretreatment of mice with phenindione also attenuated AAI-induced nephrotoxicity. These results indicate that NQO1 plays an important role in renal AAI nitroreduction and may thus contribute to AAI-induced nephrotoxicity.
