Cholera toxin-induced PGE(2) activity is reduced by chemical reaction with L-histidine.
Mediators of cholera toxin (CT)-induced fluid secretion include 3',5'-adenosine monophosphate (cAMP), prostaglandin E(2) (PGE(2)), and 5-hydroxytryptamine (5-HT). Administration of L-histidine significantly reduced the net secretory response of the small intestine of mice challenged with CT and reduced the capacity of PGE(2) to stimulate Na+ transport in Ussing chambers. We demonstrated that L-histidine chemically modified the structure of PGE(2) but had no direct effect on cAMP or 5-HT. L-Histidine and imidazole reacted with PGE(2) in vitro in cell-free mixtures incubated at 37 degrees C and pH 7.0 under an atmosphere of N(2) with the formation of PGE(2)-imidazole and PGE(2)-histidine covalent adducts. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) analysis of the purified adduct showed that imidazole catalyzed the dehydration of PGE(2). A Michael adduct then was formed between C11 of 11-deoxy-Delta(10) PGE(2) (PGA(2)) and the tau nitrogen in the imidazole ring of L-histidine. Importantly, the isolated PGE(2)-imidazole and PGE(2)-histidine adducts inhibited CT-induced fluid loss and cAMP accumulation in mouse intestinal loops. The protection provided by PGE(2)-imidazole, PGE(2)-histidine, and L-histidine against intestinal fluid loss could provide a basis for future therapy against cholera.
Peterson
J W
JW
Department of Microbiology and Immunology, Center for Tropical Diseases, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1070, USA. johnny.peterson@utmb.edu
King
D
D
Ezell
E L
EL
Rogers
M
M
Gessell
D
D
Hoffpauer
J
J
Reuss
L
L
Chopra
A K
AK
Gorenstein
D
D
D000818:Animals; D001665:Binding Sites; D001826:Body Fluids / Q000737:chemistry; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002771:Cholera / Q000188:drug therapy / Q000503:physiopathology*; D002772:Cholera Toxin / Q000037:antagonists & inhibitors; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006639:Histidine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure
D007093:Imidazoles; D006639:Histidine; C029899:imidazole; D002772:Cholera Toxin; D000242:Cyclic AMP; D015232:Dinoprostone