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Ivermectin is a nonselective inhibitor of mammalian P-type ATPases
Paulo Henrique Cotrim Pimenta1, Claudia Lucia Martins Silva, François Noël
1Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Bloco J do Centro de Ciências da Saúde, sala 17, Universidade Federal do Rio de Janeiro, Cidade Universitária, Av. Carlos Chagas Filho, 373, CEP: 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil.
Abstract:
Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na(+) , K(+)-ATPase and H(+)/K(+)-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na(+), K(+)-ATPase in order to appreciate its putative selectivity towards the alpha(1) isoform (kidney) and the alpha(2)/alpha(3) isoforms (brain), and in an H(+)/K(+)-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC(50) values (6-17 microM). With respect to the inhibition of the Na(+), K(+)-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K(+) and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.
Insights
Ivermectin, a safe antiparasitic, inhibits key cellular pumps like SERCA, Na(+), K(+)-ATPase, and H(+)/K(+)-ATPase at high doses. This nonselective inhibition suggests potential adverse effects, necessitating new drug analogs.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Ivermectin is a broad-spectrum antiparasitic agent known for its safety at therapeutic doses.
- Emerging research into new applications for ivermectin necessitates understanding its effects at higher concentrations.
- Previous studies indicated ivermectin's inhibitory effect on sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) at micromolar concentrations.
Purpose of the Study:
- To investigate the inhibitory effects of ivermectin on Na(+), K(+)-ATPase and H(+)/K(+)-ATPase.
- To extend existing data on ivermectin's inhibition of SERCA isoforms (SERCA1a and 1b).
- To assess the selectivity of ivermectin towards different isoforms of Na(+), K(+)-ATPase (alpha1, alpha2/alpha3).
Main Methods:
- Utilized rat-enriched preparations for SERCA1a and 1b isoforms.
- Tested ivermectin's effects on rat Na(+), K(+)-ATPase (kidney and brain isoforms) and rat stomach H(+)/K(+)-ATPase.
- Determined IC(50) values for ivermectin's inhibition of these P-type ATPases.
Main Results:
- Ivermectin demonstrated nonselective inhibition across all tested P-type ATPases (SERCA, Na(+), K(+)-ATPase, H(+)/K(+)-ATPase) with similar IC(50) values ranging from 6-17 microM.
- The mechanism of Na(+), K(+)-ATPase inhibition by ivermectin differs from cardiac glycosides, showing isoform selectivity and sensitivity to potassium ions and ionic conditions.
- Ivermectin's inhibition is independent of enzyme conformation and K+ antagonism.
Conclusions:
- Ivermectin acts as a nonselective inhibitor of key mammalian P-type ATPases at higher concentrations.
- This nonselective inhibition indicates potential significant adverse effects if ivermectin is used at elevated doses.
- Development of novel ivermectin analogs is recommended, evaluating both antiparasitic activity and in vitro effects on P-type ATPases.
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