title: Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11-7082, parthenolide and dimethyl fumarate.
abstract: In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11-7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11-7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11-7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach "Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target" (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity.
authors.affiliation: Psoriasis-Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 7, Kiel, 24105, Germany.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Ghashghaeinia
authors.affiliation: Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Via A Moro 2, 53100, Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giustarini
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry Palacky University, Hnevotinska 3, 77515 Olomouc, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Koralkova
authors.affiliation: Department of Dermatology and Allergy, Biedersteinerstr. 29, Technische Universität München, 80802 München, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Köberle
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Kousi
authors.initials: K
authors.lastname: Alzoubi
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Rosi
authors.initials: R
authors.lastname: Bissinger
authors.affiliation: Centre for Ophthalmology, Institute for Ophthalmic Research, Eberhard-Karls-University Tübingen, Frondsbergstr. 23, 72076 Tübingen, Germany.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Hosseinzadeh
authors.affiliation: Institute of Physiology II, Keplerstr. 15, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dreischer
authors.affiliation: Laboratory of Biophysics, Saarland University, Campus A2.4, 66123 Saarbrücken, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Bernhardt
authors.affiliation: Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Roentgenweg 11, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
authors.affiliation: Department of Dermatology; Eberhard Karls University, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry Palacky University, Hnevotinska 3, 77515 Olomouc, Czech Republic.
authors.forename: Renata
authors.initials: R
authors.lastname: Mojzikova
authors.affiliation: Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Via A Moro 2, 53100, Siena, Italy.
authors.forename: Ranieri
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Psoriasis-Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 7, Kiel, 24105, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mrowietz
mesh_terms: D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D000072817:Eryptosis / Q000187:drug effects*; D004912:Erythrocytes / Q000201:enzymology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009570:Nitriles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D009570:Nitriles; D012717:Sesquiterpenes; D013450:Sulfones; C002669:parthenolide; D005954:Glucosephosphate Dehydrogenase; D000069462:Dimethyl Fumarate