Crucial role of carbon monoxide as a regulator of diarrhea caused by cholera toxin: Evidence of direct interaction with toxin

Lorena Duarte da Silva; João Lucas Silva Pinheiro; Lucas Henrique Marques Rodrigues; Victória Martins Rodrigues Dos Santos; Jamille Lauanne Felinto Borges; Raiany Rodrigues de Oliveira; Larissa Gonçalves Maciel; Thiago de Souza Lopes Araújo; Conceição da Silva Martins; Dayane Aparecida Gomes; Eduardo Carvalho Lira; Marcellus Henrique Loiola Ponte Souza; Jand Venes Rolim Medeiros; Renan Oliveira Silva Damasceno

doi:10.1016/j.bcp.2023.115791

Crucial role of carbon monoxide as a regulator of diarrhea caused by cholera toxin: Evidence of direct interaction with toxin

Biochem Pharmacol. 2023 Oct:216:115791. doi: 10.1016/j.bcp.2023.115791. Epub 2023 Sep 7.

Authors

Lorena Duarte da Silva¹, João Lucas Silva Pinheiro¹, Lucas Henrique Marques Rodrigues¹, Victória Martins Rodrigues Dos Santos¹, Jamille Lauanne Felinto Borges¹, Raiany Rodrigues de Oliveira¹, Larissa Gonçalves Maciel², Thiago de Souza Lopes Araújo³, Conceição da Silva Martins⁴, Dayane Aparecida Gomes¹, Eduardo Carvalho Lira¹, Marcellus Henrique Loiola Ponte Souza⁵, Jand Venes Rolim Medeiros³, Renan Oliveira Silva Damasceno⁶

Affiliations

¹ Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, PE, Brazil.
² Department of Fundamental Chemistry, Federal University of Pernambuco, Recife, PE, Brazil.
³ Biotechnology and Biodiversity Center Research, Parnaíba Delta Federal University, Parnaíba, PI, Brazil.
⁴ Department of Morphology, Federal University of Ceará, Fortaleza, CE, Brazil.
⁵ Department of Physiology and Pharmacology, Federal University of the Parnaiba Delta, Fortaleza, CE, Brazil.
⁶ Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, PE, Brazil. Electronic address: renan.oliveirasilva@ufpe.br.

PMID: 37689274
DOI: 10.1016/j.bcp.2023.115791

Abstract

The present study evaluated the role of heme oxygenase 1 (HO-1)/carbon monoxide (CO) pathway in the cholera toxin-induced diarrhea and its possible action mechanism. The pharmacological modulation with CORM-2 (a CO donor) or Hemin (a HO-1 inducer) decreased the intestinal fluid secretion and Cl^- efflux, altered by cholera toxin. In contrast, ZnPP (a HO-1 inhibitor) reversed the antisecretory effect of Hemin and potentiated cholera toxin-induced intestinal secretion. Moreover, CORM-2 also prevented the alteration of intestinal epithelial architecture and local vascular permeability promoted by cholera toxin. The intestinal absorption was not altered by any of the pharmacological modulators. Cholera toxin inoculation also increased HO-1 immunoreactivity and bilirubin levels, a possible protective physiological response. Finally, using fluorometric technique, ELISA assay and molecular docking simulations, we show evidence that CO directly interacts with cholera toxin, forming a complex that affects its binding to GM1 receptor, which help explain the antisecretory effect. Thus, CO is an essential molecule for protection against choleric diarrhea and suggests its use as a possible therapeutic tool.

Keywords: Carbon monoxide; Cholera toxin; Diarrhea.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbon Monoxide* / metabolism
Cholera Toxin* / toxicity
Diarrhea / chemically induced
Diarrhea / drug therapy
Heme Oxygenase-1 / metabolism
Hemin
Humans
Molecular Docking Simulation

Substances

Cholera Toxin
tricarbonyldichlororuthenium (II) dimer
Carbon Monoxide
Hemin
Heme Oxygenase-1