Vukomanovic Dragic, Rahman Mona N, Bilokin Yaroslav, Golub Andriy G, Brien James F, Szarek Walter A, Jia Zongchao, Nakatsu Kanji
Department of Biomedical & Molecular Sciences, School of Medicine, Queen's University, Kingston, ON K7L 3 N6, Canada.
Med Gas Res. 2014 Feb 18;4(1):4. doi: 10.1186/2045-9912-4-4.
Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure-activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy.
Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and -2, respectively, as well as recombinant, human heme oxygenase-2.
Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and -3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, α-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase.
These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties.
此前，我们报道过甲萘醌可选择性激活大鼠天然血红素加氧酶-2（HO-2）和人重组血红素加氧酶-2；它不会激活脾脏微粒体血红素加氧酶-1。本研究的目的是探究这种激活作用的一些构效关系，以及氧化还原特性可能是甲萘醌疗效重要方面的观点。
分别以大鼠脾脏和脑微粒体作为血红素加氧酶-1和-2的来源，以及重组人血红素加氧酶-2，在体外测定血红素加氧酶活性。
在3位带有庞大脂肪族基团的甲萘醌类似物，即维生素K1和K2，无法激活HO-2。相比之下，几种在2位（和3位）带有类似庞大但亲脂性较低基团的化合物能够将HO-2激活数倍；这些化合物包括极性、刚性、含呋喃的萘醌、呋喃-苯并恶嗪萘醌、2-(氨基苯基苯基)-3-哌啶-1-基萘醌。为探究氧化还原特性可能与甲萘醌疗效有关的观点，我们测试了诸如1,4-二甲氧基-2-甲基萘、五氟甲萘醌、单卤代萘醌、α-四氢萘酮和1,4-萘醌等类似物。除1,4-萘醌外，所有这些化合物均无活性。甲萘醌激活全长重组人血红素加氧酶-2（FL-hHO-2）的效果与大鼠脑酶相同，但它不会激活大鼠脾脏血红素加氧酶。
这些观察结果与如下观点一致，即甲萘醌之类的萘醌与HO-2中的一种受体结合，并通过一种可能涉及氧化还原特性的机制激活该酶。
