title: In vitro Activation of heme oxygenase-2 by menadione and its analogs.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Dragic
authors.initials: D
authors.lastname: Vukomanovic
authors.forename: Mona N
authors.initials: MN
authors.lastname: Rahman
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Bilokin
authors.forename: Andriy G
authors.initials: AG
authors.lastname: Golub
authors.forename: James F
authors.initials: JF
authors.lastname: Brien
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Biomedical & Molecular Sciences, School of Medicine, Queen's University, Kingston, ON K7L 3 N6, Canada. nakatsuk@queensu.ca.
authors.forename: Kanji
authors.initials: K
authors.lastname: Nakatsu