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Effects of Phenothiazines on Aldehyde Oxidase Activity Towards Aldehydes and N-Heterocycles: an In Vitro and In Silico Study

  • Farnaz Deris Abdolahpour
  • Lida Abolaliporan Sadegh
  • Siavoush Dastmalchi
  • Maryam Hamzeh-Mivehroud
  • Omid Zarei
  • Gholamreza Dehgan
  • Mohammad-Reza RashidiEmail author
Original Research Article
  • 49 Downloads

Abstract

Background

Aldehyde oxidase (AOX) is an important molybdenum-containing enzyme with high similarity with xanthine oxidase (XO). AOX involved in the metabolism of a large array of aldehydes and N-heterocyclic compounds and its activity is highly substrate-dependent.

Objectives

The aim of this work was to study the effect of five important phenothiazine drugs on AOX activity using benzaldehyde and phenanthridine as aldehyde and N-heterocyclic substrates, respectively.

Methods

The effect of trifluperazine, chlorpromazine, perphenazine, thioridazine and promethazine on rat liver AOX was measured spectrophotometrically. To predict the mode of interactions between the studied compounds and AOX, a combination of homology modeling and a molecular docking study was performed.

Results

All phenothiazines could inhibit AOX activity measured either by phenanthridine or benzaldehyde with almost no effect on XO activity. In the case of benzaldehyde oxidation, the lowest and highest half-maximal inhibitory concentration (IC50) values were obtained for promethazine (IC50 = 0.9 µM), and trifluoperazine (IC50 = 3.9 µM), respectively; whereas perphenazine (IC50 = 4.3 µM), and trifluoperazine (IC50 = 49.6 µM) showed the strongest and weakest inhibitory activity against AOX-catalyzed phenanthridine oxidation, respectively. The in silico findings revealed that the binding site of thioridazine is near the dimer interference, and that hydrophobic interactions are of great importance in all the tested phenothiazines.

Conclusion

The five studied phenothiazine drugs showed dual inhibitory effects on AOX activity towards aldehydes and N-heterocycles as two major classes of enzyme substrates. Most of the interactions between the phenothiazine-related drugs and AOX in the binding pocket showed a hydrophobic nature.

Notes

Acknowledgements

The work was a part of a MSc thesis and the authors are grateful to the School of Pharmacy and Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, for providing the necessary facilities during this work.

Compliance with Ethical Standards

Funding

No funding was received for the conduct of this study.

Conflict of Interest

All the authors have no conflict of interest to declare.

Ethics Approval

The study was approved by the local and national ethics committees.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Farnaz Deris Abdolahpour
    • 1
  • Lida Abolaliporan Sadegh
    • 1
  • Siavoush Dastmalchi
    • 2
    • 3
  • Maryam Hamzeh-Mivehroud
    • 2
    • 3
  • Omid Zarei
    • 4
    • 5
  • Gholamreza Dehgan
    • 1
  • Mohammad-Reza Rashidi
    • 3
    • 6
    Email author
  1. 1.Department of Zoology, Faculty of Natural ScienceUniversity of TabrizTabrizIran
  2. 2.Biotechnology Research CenterTabriz University of Medical SciencesTabrizIran
  3. 3.School of PharmacyTabriz University of Medical SciencesTabrizIran
  4. 4.Neurosciences Research CenterKurdistan University of Medical SciencesSanandajIran
  5. 5.Cellular and Molecular Research Center, Research Institute for Health DevelopmentKurdistan University of Medical SciencesSanandajIran
  6. 6.Research Center for Pharmaceutical NanotechnologyTabriz University of Medical SciencesTabrizIran

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