In vitroActivation of heme oxygenase-2 by menadione and its analogsReportar como inadecuado

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Medical Gas Research

, 4:4

Medical gas in other fields of biology


BackgroundPreviously, 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.

MethodsHeme 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.

ResultsMenadione 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.

ConclusionsThese 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.

KeywordsHeme oxygenase Enzyme activator Menadione Agonist In vitro Redox properties AbbreviationsHOHeme oxygenase

HO-1Heme oxygenase-1

HO-2Heme oxygenase-2

hHO-2Recombinant human heme oxygenase-2

ZnPPZinc protoporphyrin

SnPPTin protoporphyrin.

Electronic supplementary materialThe online version of this article doi:10.1186-2045-9912-4-4 contains supplementary material, which is available to authorized users.

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Autor: Dragic Vukomanovic - Mona N Rahman - Yaroslav Bilokin - Andriy G Golub - James F Brien - Walter A Szarek - Zongchao Jia


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