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Eur J Drug Metab Pharmacokinet. 2019 Apr;44(2):275-286. doi: 10.1007/s13318-018-0514-6.

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

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Department of Zoology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran.
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Neurosciences Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, 51664-14766, Iran.



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.


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.


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.


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.


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.

[Indexed for MEDLINE]

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