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

• Published in: Biochemical pharmacology Vol. 216; p. 115791
• Main Authors: Silva, Lorena Duarte da, Pinheiro, João Lucas Silva, Rodrigues, Lucas Henrique Marques, Santos, Victória Martins Rodrigues dos, Borges, Jamille Lauanne Felinto, Oliveira, Raiany Rodrigues de, Maciel, Larissa Gonçalves, Araújo, Thiago de Souza Lopes, Martins, Conceição da Silva, Gomes, Dayane Aparecida, Lira, Eduardo Carvalho, Souza, Marcellus Henrique Loiola Ponte, Medeiros, Jand Venes Rolim, Damasceno, Renan Oliveira Silva
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2023
• Subjects: Carbon monoxide; Cholera toxin; Diarrhea; NO; GI; DSS; HO; PKA; Diarrhea; H2S; GM1; HO-1; cAMP; CO; TNBS; ASA; ΔGbinding; CTB; CTA; CORM; Carbon monoxide; Cholera toxin; CFTR
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2023.115791

[Display omitted] 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.