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

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.

authors

Deris-Abdolahpour F,Abdolalipouran-Sadegh L,Dastmalchi S,Hamzeh-Mivehroud M,Zarei O,Dehgan G,Rashidi MR

doi

10.1007/s13318-018-0514-6

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

275-286

issue

2

eissn

0378-7966

issn

2107-0180

pii

10.1007/s13318-018-0514-6

journal_volume

44

pub_type

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