Structure-activity relationships for growth inhibition and induction of apoptosis by 4-hydroxy-2-nonenal in raw 264.7 cells

Robin L. Haynes, Luke Szweda, Kerry Pickin, Mark E. Welker, Alan J. Townsend

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Abstract

4-Hydroxy-2-nonenal (HNE) is a highly reactive lipid aldehyde byproduct of the peroxidation of cellular membranes. The structure of HNE features three functional groups, a C1 aldehyde, a C2=C3 double bond, and a C4- hydroxyl group, each of which may contribute to the toxicity of the compound. In addition, the length of the aliphatic chain may influence toxic potency by altering lipophilicity. Using analogous compounds that lacked one or more of the structural moieties, the role of each of these structural motifs in the cytotoxicity of HNE was examined in a mouse alveolar macrophage cell line (RAW 264.7) by a cell survival and growth assay. The importance of these functional groups in the potency of HNE for induction of apoptosis was also examined. The rank order of effects on toxicity was C1 - aldehyde ≥ C2≃C3 double bond >> C4 - hydroxyl, with parallel results in both the survival/growth inhibition and apoptosis induction assays. The chain length also influenced toxicity in a series of α,β-unsaturated alkenyl aldehydes, with increasing chain length yielding increasing toxicity. To confirm the importance of the aldehyde moiety, and to examine the role of metabolic detoxification in cellular defenses against HNE toxicity, a RAW 264.7 cell line overexpressing human aldehyde dehydrogenase-3 (hALDH3) was generated. This cell line exhibited nearly complete protection against HNE-protein adduct formation as well as HNE-induced apoptosis. These results illustrate the comparative significance of key structural features of HNE in relation to its potent toxicity and induction of apoptosis.

Original languageEnglish (US)
Pages (from-to)788-794
Number of pages7
JournalMolecular Pharmacology
Volume58
Issue number4
StatePublished - Oct 21 2000

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Structure-Activity Relationship
Apoptosis
Aldehydes
Growth
Hydroxyl Radical
Alveolar Epithelial Cells
Cell Line
4-hydroxy-2-nonenal
Poisons
Alveolar Macrophages
Cell Survival
Lipids
Membranes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Structure-activity relationships for growth inhibition and induction of apoptosis by 4-hydroxy-2-nonenal in raw 264.7 cells. / Haynes, Robin L.; Szweda, Luke; Pickin, Kerry; Welker, Mark E.; Townsend, Alan J.

In: Molecular Pharmacology, Vol. 58, No. 4, 21.10.2000, p. 788-794.

Research output: Contribution to journalArticle

Haynes, Robin L. ; Szweda, Luke ; Pickin, Kerry ; Welker, Mark E. ; Townsend, Alan J. / Structure-activity relationships for growth inhibition and induction of apoptosis by 4-hydroxy-2-nonenal in raw 264.7 cells. In: Molecular Pharmacology. 2000 ; Vol. 58, No. 4. pp. 788-794.
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