title: Enantioselective metabolism of trans-4-hydroxy-2-nonenal by brain mitochondria.
abstract: Trans-4-hydroxy-2-nonenal (HNE) is a product of lipid peroxidation with many cellular effects. HNE possesses a stereogenic center at the C4 carbon that influences the metabolism and alkylation targets of HNE. We tested the hypothesis that rat brain mitochondria metabolize HNE in an enantioselective manner after exposure to racemic HNE. The study of HNE chirality, however, is hindered by the lack of facile methods to chromatographically resolve (R)-HNE and (S)-HNE. We used a chiral hydrazine, (S)-carbidopa, as a derivatization reagent to form diastereomers with (R)-HNE and (S)-HNE that were separated by reverse-phase HPLC. After exposure to racemic HNE, rat brain mitochondria metabolized HNE enantioselectively with a higher rate of (R)-HNE metabolism. By using the purified enantiomers of HNE, we found that this enantioselective metabolism of HNE was the result of higher rates of enzymatic oxidation of (R)-HNE by aldehyde dehydrogenases compared to (S)-HNE. Conjugation of HNE to glutathione was a minor metabolic pathway and was not enantioselective. These studies demonstrate that the chirality of HNE affects its mitochondrial metabolism and potentially other processes in the central nervous system.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202-9024, USA.
authors.forename: Ales
authors.initials: A
authors.lastname: Honzatko
authors.forename: Jiri
authors.initials: J
authors.lastname: Brichac
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Murphy
authors.forename: Alexander
authors.initials: A
authors.lastname: Reberg
authors.forename: Alena
authors.initials: A
authors.lastname: Kubátová
authors.forename: Irina P
authors.initials: IP
authors.lastname: Smoliakova
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Picklo
mesh_terms: D000447:Aldehydes / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000648:ultrastructure*; D002230:Carbidopa / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006880:Hydroxy Acids / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: C091766:4-hydroxy-2-nonenoic acid; D000447:Aldehydes; D006880:Hydroxy Acids; C027576:4-hydroxy-2-nonenal; D002230:Carbidopa