title: Stereoselective effects of 4-hydroxynonenal in cultured mouse hepatocytes.
abstract: 4-Hydroxynonenal (HNE) is produced from arachidonic acid or linoleic acid during oxidative stress. Although HNE is formed in tissues as a racemate, enantiospecific HNE effects have not been widely documented, nor considered. Therefore, a panel of cellular responses was compared after treatment with (R)-HNE, (S)-HNE, or racemic HNE. The phosphorylation status of Jun kinase (JNK) or Akt increased 28-fold or 2-3-fold, respectively, after treatment with 100 μM (S)-HNE and racemic HNE compared to (R)-HNE. In contrast, the increase in phosphorylation of MAPK was greatest for (R)-HNE. Caspase-3-dependent cleavage of the glutamate cysteine ligase (GCL) catalytic subunit and focal adhesion kinase (FAK) were greater in cells treated with (S)-HNE at 48 h. (S)-HNE also caused a greater number of subG1 nuclei, a hallmark of apoptosis, at 30 h after treatment. Together, the results demonstrate different dose- and time-dependent responses to (R)-HNE and (S)-HNE. The results further suggest that HNE enantiomers could differentially contribute to the progression of different diseases or contribute by different mechanisms.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195-7610, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dabrowski
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Zolnerciks
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Balogh
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Greene
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.forename: William M
authors.initials: WM
authors.lastname: Atkins
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005721:Glutamate-Cysteine Ligase; C027576:4-hydroxy-2-nonenal