<abstract xmlns="http://www.w3.org/1999/xhtml">

Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1<italic>R</italic>,2<italic>S</italic>-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 <italic>IC</italic>50 at 19 mmol L−1, demonstrating a significant effect of Mox on APE1 activity in clinically relevant concentrations.
</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.

α1-Adrenoceptor agonist methoxamine inhibits base excision repair <italic>via</italic> inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)

Faculty of Medicine, Department of Biology

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

α-Adrenoceptor agonist methoxamine inhibits base excision repair  inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)

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...

α₁-Adrenoceptor agonist methoxamine inhibits base excision repair via inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)

Publicado en línea: 12 jun 2023

Páginas: 281 - 291

Aceptado: 25 oct 2022

DOI: https://doi.org/10.2478/acph-2023-0012

Palabras clave
methoxamine, base excision repair, apurinic/apyrimidinic endonuclease APE1, α1-adrenoceptor agonist

© 2023 Aneta Kohutova et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

α1-Adrenoceptor agonist methoxamine inhibits base excision repair via inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)

Publicado en línea: 12 jun 2023

Páginas: 281 - 291

Aceptado: 25 oct 2022

DOI: https://doi.org/10.2478/acph-2023-0012

Palabras clavemethoxamine, base excision repair, apurinic/apyrimidinic endonuclease APE1, α1-adrenoceptor agonist

© 2023 Aneta Kohutova et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

α₁-Adrenoceptor agonist methoxamine inhibits base excision repair via inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)

Palabras clave
methoxamine, base excision repair, apurinic/apyrimidinic endonuclease APE1, α1-adrenoceptor agonist