title: NADPH oxidase inhibitor, apocynin, improves renal glutathione status in Zucker diabetic fatty rats: a comparison with melatonin.
abstract: Apocynin (4'-hydroxy-3'-methoxyacetophenone) is the most commonly used NADPH oxidase (Nox) inhibitor. However, its application raises serious controversies, as the compound has been reported to reveal some prooxidative effects. The aim of this study was to elucidate apocynin action on glutathione, the main intracellular antioxidant, metabolism in kidneys of Zucker diabetic fatty (ZDF) rat, a well established model of diabetes type 2. Additionally, apocynin effects were compared with those of melatonin. The experiments were performed on five groups of animals: (1) untreated lean (?/+) ZDF rats, (2) ZDF ?/+ rats treated with apocynin (2 g/l) in drinking water, (3) untreated obese diabetic (fa/fa) ZDF rats, (4) ZDF fa/fa rats treated with apocynin (2 g/l) in drinking water, and (5) ZDF fa/fa rats treated with melatonin (20 mg/l) in drinking water. After 8weeks of the treatment, the following parameters were measured in kidneys: NADPH oxidase activity, the rate of hydroxyl free radicals (HFR) production, GSH and GSSG content and the activities of the enzymes of glutathione metabolism: γ-glutamylcysteine synthetase (GCS), glutathione reductase (GR) and glutathione peroxidase (GPx). Compared to ?/+ controls, ZDF fa/fa rats exhibited increased Nox activity, accelerated HFR generation and dramatically lowered GSH/GSSG ratio accompanied by increased GPx and diminished GCS activities. In case of diabetic animals, apocynin treatment resulted in attenuation of both Nox activity and HFR production, restoration of control GSH/GSSG ratio (due to both an increase in GSH and a decline in GSSG content), normalization of GPx activity and a slight increase in GCS activity. Similar observations were made upon melatonin application to ZDF fa/fa rats. Thus, it is concluded that, in the diabetic model studied, apocynin extends a beneficial effect on renal glutathione homeostasis. The mechanism of this phenomenon involves attenuation of glutathione peroxidase activity, which is overstimulated under conditions of oxidative stress accompanying diabetes.
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland. Electronic address: k.winiarska@biol.uw.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Winiarska
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Focht
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Sierakowski
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Krystian
authors.initials: K
authors.lastname: Lewandowski
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Orlowska
authors.affiliation: Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, I. Miecznikowa 1, 02-096 Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Usarek
mesh_terms: D000098:Acetophenones / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000652:urine; D005979:Glutathione Peroxidase / Q000652:urine; D005980:Glutathione Reductase / Q000652:urine; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009765:Obesity; D051381:Rats; D011924:Rats, Zucker
chemical_list: D000098:Acetophenones; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D017665:Hydroxyl Radical; C056165:acetovanillone; D005979:Glutathione Peroxidase; D019255:NADPH Oxidases; D005980:Glutathione Reductase; D005978:Glutathione; D008550:Melatonin
keywords: Apocynin; Glutathione; Kidney; Melatonin; NADPH oxidase; ZDF rat