title: Glitazones inhibit human monoamine oxidase but their anti-inflammatory actions are not mediated by VAP-1/semicarbazide-sensitive amine oxidase inhibition.
abstract: Glitazones are peroxisome proliferator-activated receptor gamma (PPARγ) agonists widely used as antidiabetic drugs also known as thiazolidinediones. Most of them exert other effects such as anti-inflammatory actions via mechanisms supposed to be independent from PPARγ activation (e.g., decreased plasma monocyte chemoattractant protein-1 (MCP-1) levels). Recently, pioglitazone has been shown to inhibit the B form of monoamine oxidase (MAO) in mouse, while rosiglitazone and troglitazone were described as non-covalent inhibitors of both human MAO A and MAO B. Since molecules interacting with MAO might also inhibit semicarbazide-sensitive amine oxidase (SSAO), known as vascular adhesion protein-1 (VAP-1), and since VAP-1/SSAO inhibitors exhibit anti-inflammatory activity, our aim was to elucidate whether VAP-1/SSAO inhibition could be a mechanism involved in the anti-inflammatory behaviour of glitazones. To this aim, MAO and SSAO activities were measured in human subcutaneous adipose tissue biopsies obtained from overweight women undergoing plastic surgery. The production of hydrogen peroxide, an end-product of amine oxidase activity, was determined in tissue homogenates using a fluorometric method. The oxidation of 1 mM tyramine was inhibited by pargyline and almost resistant to semicarbazide, therefore predominantly MAO-dependent. Rosiglitazone was more potent than pioglitazone in inhibiting tyramine oxidation. By contrast, benzylamine oxidation was only abolished by semicarbazide: hence SSAO-mediated. Pioglitazone hampered SSAO activity only when tested at 1 mM while rosiglitazone was inefficient. However, rosiglitazone exhibited anti-inflammatory activity in human adipocytes by limiting MCP-1 expression. Our observations rule out any involvement of VAP-1/SSAO inhibition and subsequent limitation of leukocyte extravasation in the anti-inflammatory action of glitazones.
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale (INSERM U1048), Toulouse, France, christian.carpene@inserm.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Carpéné
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bizou
authors.forename: Karine
authors.initials: K
authors.lastname: Tréguer
authors.forename: Mounia
authors.initials: M
authors.lastname: Hasnaoui
authors.forename: Sandra
authors.initials: S
authors.lastname: Grès
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000328:Adult; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001596:Benzylamines / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D000077205:Pioglitazone; D000077154:Rosiglitazone; D050151:Subcutaneous Fat / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology*; D014439:Tyramine / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001596:Benzylamines; D015815:Cell Adhesion Molecules; D008996:Monoamine Oxidase Inhibitors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C030796:benzylamine; D006861:Hydrogen Peroxide; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D000077205:Pioglitazone; D014439:Tyramine