Molecular Mechanisms of 4-Hydroxy-2-nonenal and Acrolein Toxicity: Nucleophilic Targets and Adduct Formation

Abstract

Acrolein and 4-hydroxy-2-nonenal (HNE) are by-products of lipid peroxidation and are thought to play central roles in various traumatic injuries and disease states that involve cellular oxidative stress; e.g., spinal cord trauma, diabetes, Alzheimer's disease. In this Commentary, 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 pi 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. Based on 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.

AKR1B10 overexpression in breast cancer: Association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker

“…They are highly electrophilic and can induce protein dysfunction, DNA damage and apoptosis. 31,32 AKR1B10 can efficiently detoxify the cellular carbonyls and their glutathione conjugates by reducing the reactive carbonyl groups into less active hydroxyls. 6 Therefore, AKR1B10 may protect host cells from carbonyl lesions, promoting cell growth and survival.…”

Possible Involvement of Transient Receptor Potential Channels in Electrophile-Induced Insulin Secretion from RINm5F Cells

“…30) 4-HNE also reacts with primary amino groups to form Schiff base linkages. 30) These protein modifications disrupt cell function and thus exert a cytotoxic effect.…”

“…30) 4-HNE also reacts with primary amino groups to form Schiff base linkages. 30) These protein modifications disrupt cell function and thus exert a cytotoxic effect. On the other hand, 4-HNE modification of particular proteins alters the intracellular signaling and induces the expression of certain sets of genes, indicating that the aldehyde may function as a second messenger in cells.…”

Protective effects of the aqueous extract ofScutellaria baicalensisagainst acrolein-induced oxidative stress in cultured human umbilical vein endothelial cells

“…Acrolein is a highly reactive unsaturated aldehydic product of lipid peroxidation that could implicate various degenerative pathogenesis, oxidative DNA damage and mutagenesis and is widely used as a positive control of reactive oxygen species (ROS) experiments (Jia et al, 2007;LoPachin et al, 2009;Luo & Shi, 2005;Pan et al, 2009;Roy et al, 2009;Wang et al, 2009;Zitting & Heinonen, 1980). However, protection against acrolein toxicity in endothelial cells by using the aqueous extract of Scutellaria baicalensis Georgi (Labiatae) (SbG) has not been investigated, though SbG has been reported to have anti-asthmatic, anti-fungal, antioxidative, and antiinflammatory activities (Huang et al, 2006;Koda et al, 1972;Wong & Tsang, 2009).…”