Acta Pharmaceutica, Vol. 73 No. 2, 2023.
Original scientific paper
https://doi.org/10.2478/acph-2023-00xx
α1-Adrenoceptor agonist methoxaminen inhibits base excision repair via inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)
ANETA KOHUTOVA
; Masaryk University, Faculty of Medicine, Department of Biology, 625 00, Brno, Czech Republic
DITA MÜNZOVA
; Masaryk University, Faculty of Medicine, Department of Biology, 625 00, Brno, Czech Republic
MARTIN PEŠL
; Masaryk University, Faculty of Medicine, Department of Biology, 625 00, Brno, Czech Republic; International Clinical Research Center (ICRC), St.Anne’s University hospital in Brno, 625 00, Brno, Czech Republic
VLADIMIR ROTREKL
; Masaryk University, Faculty of Medicine, Department of Biology, 625 00, Brno, Czech Republic; International Clinical Research Center (ICRC), St.Anne’s University hospital in Brno, 625 00, Brno, Czech Republic
Abstract
Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1R,2S-Mox (NRL001) has been also undergoing clinical testing to increase the canal resting pressure in patients with bowel incontinence. Here we show, that Mox hydrochloride acts as an inhibitor of base excision repair (BER). The effect is mediated by the inhibition of apurinic/apyrimidinic endonuclease APE1. We link this observation to our previous report showing the biologically relevant effect of Mox on BER – prevention of converting oxidative DNA base damage to double-stranded breaks. We demonstrate that its effect is weaker, but still significant when compared to a known BER inhibitor methoxyamine (MX). We further determined Mox’s relative IC50 at 19 mmol L–1, demonstrating a significant effect of Mox on APE1 activity in clinically relevant concentrations.
Keywords
methoxamine; base excision repair; apurinic/apyrimidinic endonuclease APE1; α1-adrenoceptor agonist
Hrčak ID:
284917
URI
Publication date:
30.6.2023.
Visits: 259 *