Dračínská Helena, Bárta František, Levová Kateřina, Hudecová Alena, Moserová Michaela, Schmeiser Heinz H, Kopka Klaus, Frei Eva, Arlt Volker M, Stiborová Marie
Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Toxicology. 2016 Feb 17;344-346:7-18. doi: 10.1016/j.tox.2016.01.011. Epub 2016 Feb 1.
Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic
NAD(P)H: quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the (32)P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts.
马兜铃酸I（AAI）是一种天然植物生物碱，可导致马兜铃酸肾病、巴尔干地方性肾病及其相关的尿路上皮恶性肿瘤。将AAI还原激活为形成AAI-DNA加合物的物种的最有效酶之一是胞质NAD(P)H：醌氧化还原酶1。AAI还可通过微粒体细胞色素P450（CYP）1A1和1A2被还原激活或氧化解毒为8-羟基马兜铃酸（AAIa）。在此，我们研究了这两种相反的CYP1A1/2催化反应中哪一种在AAI体内代谢中占主导地位。在用AAI、苏丹I（CYP1A1/2的强效诱导剂）或苏丹I预处理后再用AAI处理的大鼠的肝脏、肾脏和肺中分析AAI-DNA加合物的形成。与单独用AAI处理的大鼠相比，苏丹I处理后再用AAI处理的大鼠的肝脏、肾脏和肺中，通过（32）P后标记法测定的AAI-DNA加合物水平较低。苏丹I对CYP1A1/2的诱导增加了AAI向其O-去甲基代谢物AAIa的解毒作用，从而减少了可用于还原激活的AAI的实际量。这随后导致大鼠体内AAI-DNA加合物水平降低。我们的结果表明，CYP1A1/2介导的AAI氧化解毒是这些酶在大鼠体内的主要作用，从而抑制了AAI-DNA加合物的水平。
