State Research Institute Center for Innovative Medicine, Santariškių St. 5, LT-08406 Vilnius, Lithuania.
Institute of Biochemistry of Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania.
Int J Mol Sci. 2020 Nov 19;21(22):8754. doi: 10.3390/ijms21228754.
Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP oxidoreductase (FNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and FNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O ( 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and FNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic oxides.
替拉扎胺和其他杂芳族氮氧化物（ArN→O）的衍生物具有杀肿瘤、抗菌和抗原生动物活性，这些活性通常归因于生物还原激活和自由基生成。在这项工作中，我们旨在阐明 NAD(P)H：醌氧化还原酶（NQO1）在 ArN→O 需氧细胞毒性中的作用。我们合成了 9 个具有未表征氧化还原性质的 ArN→O 代表物，并研究了它们在大鼠 NADPH：细胞色素 P-450 还原酶（P-450R）和铁氧还蛋白：NADP 氧化还原酶（FNR）以及大鼠 NQO1 作用下的单电子还原。NQO1 催化了 ArN→O 的氧化还原循环和稳定还原产物的形成。ArN→O 在 NQO1 催化反应中的反应性与它们对 P-450R 和 FNR 的活性的几何平均值不相关，后者被视为其氧化还原循环效力的参数。抗氧化剂和 NQO1 抑制剂二香豆素降低了化合物在小鼠肝癌 MH22a 细胞中的细胞毒性。对本研究和之前研究（DOI：10.3390/ijms20184602）数据的多参数回归分析表明，ArN→O（18）在 MH22a 和人结肠癌细胞 HCT-116 中的细胞毒性随其对 P-450R 和 FNR 的反应性的几何平均值以及对 NQO1 的反应性而增加。这些数据表明，NQO1 是杂芳族氧化物潜在的重要作用靶点。
