title: Astrocytic biotransformation of trans-4-hydroxy-2-nonenal is dose-dependent.
abstract: Elevated levels of trans-4-hydroxy-2-nonenal (HNE) are observed in brain tissues in patients with neurodegenerative diseases. Although astrocytes are known to play a crucial role in regulating and supporting neuronal processes, their capacity to detoxify HNE is unknown. In this work, we examined the extent to which HNE undergoes phase I and phase II metabolism in astrocytes. Murine astrocytes were exposed to three different concentrations of HNE. The loss of HNE was approximately 90%, 80%, and 70% for 1, 5, and 15 microM HNE, respectively, following a 10 min incubation. The expected metabolites trans-4-hydroxy-2-nonenoic acid (HNEAcid), (4-hydroxynonanal-3-yl)glutathione (GSHNE), and (1,4-dihydroxynonane-3-yl)glutathione (GSDHN) accounted for 90% of HNE lost at 1 microM HNE. However, when astrocytes were exposed to 5 and 15 microM HNE, those metabolites accounted only for 50% and 17%, respectively. Binding to macromolecules accounted for only 5-10% of HNE loss. Furthermore, depletion of GSH content had only a small effect on HNE metabolism without elevating HNE oxidation and suggests that other unidentified metabolic pathways are functioning. We identified two novel metabolites of HNE, gamma-nonalactone and the potent pyrrole forming compound, 4-oxo-nonanal (ONA). Occurrence of 1,4-dihydroxynonene was observed as well. These data suggest that the biotransformation of HNE yields products with differing or enhanced toxicity, as well as nontoxic products.
authors.affiliation: Department of Chemistry, University of North Dakota, Grand Forks, 58202, USA.
authors.forename: Alena
authors.initials: A
authors.lastname: Kubatova
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Murphy
authors.forename: Colin
authors.initials: C
authors.lastname: Combs
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Picklo
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure
chemical_list: D000447:Aldehydes; D007783:Lactones; D005978:Glutathione; C027576:4-hydroxy-2-nonenal