title: THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy.
abstract: Ammonia production is implicated in the pathogenesis of hepatic encephalopathy (HE), being intestinal glutaminase activity the main source for ammonia. Management of ammonia formation can be effective in HE treatment by lowering intestinal ammonia production. The use of glutaminase inhibitors represents one way to achieve this goal. In this work, we have performed a search for specific inhibitors that could decrease glutaminase activity by screening two different groups of compounds: i) a group integrated by a diverse, highly pure small molecule compounds derived from thiourea ranging from 200 to 800 Daltons; and ii) a group integrated by commonly use compounds in the treatment of HE. Results shown that THDP-17 (10 µM), a thiourea derivate product, could inhibit the intestinal glutaminase activity (57.4±6.7%). Inhibitory effect was tissue dependent, ranging from 40±5.5% to 80±7.8% in an uncompetitive manner, showing Vmax and Km values of 384.62 µmol min(-1), 13.62 mM with THDP-17 10 µM, respectively. This compound also decreased the glutaminase activity in Caco-2 cell cultures, showing a reduction of ammonia and glutamate production, compared to control cultures. Therefore, the THDP-17 compound could be a good candidate for HE management, by lowering ammonia production.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: M Mar
authors.initials: MM
authors.lastname: Díaz-Herrero
authors.affiliation: Unidad de Gestión Clínica de Enfermedades Digestivas & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Universitario de Valme, Sevilla, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: del Campo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Carbonero-Aguilar
authors.affiliation: Departamento de Química Orgánica y Química Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Vega-Pérez
authors.affiliation: Departamento de Química Orgánica y Química Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Iglesias-Guerra
authors.affiliation: Departamento de Química Orgánica y Química Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Periñán
authors.affiliation: Unidad de Farmacología Experimental y Clínica (UFEC), Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Miñano
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Bautista
authors.affiliation: Unidad de Gestión Clínica de Enfermedades Digestivas & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Universitario de Valme, Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gómez
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D018938:Caco-2 Cells; D002470:Cell Survival; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D006501:Hepatic Encephalopathy / Q000188:drug therapy*; D006801:Humans; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C000599770:THDP-17; D000641:Ammonia; D005972:Glutaminase; D013890:Thiourea