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

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A Correction to this article was published on 18 January 2019

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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.

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Change history

  • 18 January 2019

    Unfortunately, the original article was published with error in author names. The author names are corrected here by this correction paper. The original article has been corrected.

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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.

Author information

Authors and Affiliations

  1. Department of Zoology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran

    Farnaz Deris-Abdolahpour, Lida Abdolalipouran-Sadegh & Gholamreza Dehgan

  2. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Siavoush Dastmalchi & Maryam Hamzeh-Mivehroud

  3. School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Siavoush Dastmalchi, Maryam Hamzeh-Mivehroud & Mohammad-Reza Rashidi

  4. Neurosciences Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Omid Zarei

  5. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Omid Zarei

  6. Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, 51664-14766, Iran

    Mohammad-Reza Rashidi

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  1. Farnaz Deris-Abdolahpour
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  2. Lida Abdolalipouran-Sadegh
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Correspondence to Mohammad-Reza Rashidi.

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The original version of this article was revised: Author names were incorrectly published and corrected here.

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Deris-Abdolahpour, F., Abdolalipouran-Sadegh, L., Dastmalchi, S. et al. Effects of Phenothiazines on Aldehyde Oxidase Activity Towards Aldehydes and N-Heterocycles: an In Vitro and In Silico Study. Eur J Drug Metab Pharmacokinet 44, 275–286 (2019). https://doi.org/10.1007/s13318-018-0514-6

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