Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity: Nucleophilic targets and adduct formation

Richard M. LoPachin, Terrence Gavin, Dennis R. Petersen, David S. Barber

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Acrolein and 4-hydroxy-2-nonenal (HNE) are byproducts of lipid peroxidation and are thought to play central roles in various traumatic injuries and disease states that involve cellular oxidative stress, for example, spinal cord trauma, diabetes, and Alzheimer's disease. In this review, we will discuss the chemical attributes of acrolein and HNE that determine their toxicities. Specifically, these aldehydes are classified as type 2 alkenes and are characterized by an α,β-unsaturated carbonyl structure. This structure is a conjugated system that contains mobile π-electrons. The carbonyl oxygen atom is electronegative and can promote the withdrawal of mobile electron density from the β-carbon atom causing regional electron deficiency. On the basis of this type of electron polarizability, both acrolein and HNE are considered to be soft electrophiles that preferentially form 1,4-Michael type adducts with soft nucleophiles. Proteomic, quantum mechanical, and kinetic data will be presented, indicating that cysteine sulfhydryl groups are the primary soft nucleophilic targets of acrolein and HNE. This is in contrast to nitrogen groups on harder biological nucleophiles such as lysine or histidine residues. The toxicological outcome of adduct formation is not only dependent upon residue selectivity but also the importance of the targeted amino acid in protein function or structure. In attempting to discern the toxicological significance of a given adduct, we will consider the normal roles of cysteine, lysine, and histidine residues in proteins and the relative merits of corresponding adducts in the manifestations of diseases or toxic states. Understanding the molecular actions of acrolein and HNE could provide insight into many pathogenic conditions that involve initial cellular oxidative stress and could, thereby, offer new efficacious avenues of pharmacological defense.

Original languageEnglish (US)
Pages (from-to)1499-1508
Number of pages10
JournalChemical Research in Toxicology
Volume22
Issue number9
DOIs
StatePublished - Sep 21 2009

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Acrolein
Toxicity
Electrons
Nucleophiles
Oxidative stress
Histidine
Toxicology
Lysine
Cysteine
Oxidative Stress
Atoms
Poisons
Alkenes
Medical problems
Spinal Cord Injuries
Aldehydes
Proteomics
Lipid Peroxidation
Carrier concentration
Byproducts

ASJC Scopus subject areas

  • Toxicology

Cite this

Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity : Nucleophilic targets and adduct formation. / LoPachin, Richard M.; Gavin, Terrence; Petersen, Dennis R.; Barber, David S.

In: Chemical Research in Toxicology, Vol. 22, No. 9, 21.09.2009, p. 1499-1508.

Research output: Contribution to journalArticle

LoPachin, Richard M. ; Gavin, Terrence ; Petersen, Dennis R. ; Barber, David S. / Molecular mechanisms of 4-hydroxy-2-nonenal and acrolein toxicity : Nucleophilic targets and adduct formation. In: Chemical Research in Toxicology. 2009 ; Vol. 22, No. 9. pp. 1499-1508.
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