NDLI: Synaptosomal Toxicity and Nucleophilic Targets of 4-Hydroxy-2-Nonenal

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Synaptosomal Toxicity and Nucleophilic Targets of 4-Hydroxy-2-Nonenal

Content Provider	PubMed Central
Author	Lopachin, Richard M. Geohagen, Brian C. Gavin, Terrence
Copyright Year	2009
Abstract	4-Hydroxy-2-nonenal (HNE) is an aldehyde by-product of lipid peroxidation that is presumed to play a primary role in certain neuropathogenic states (e.g., Alzheimer disease, spinal cord trauma). Although the molecular mechanism of neurotoxicity is unknown, proteomic analyses (e.g., tandem mass spectrometry) have demonstrated that this soft electrophile preferentially forms Michael-type adducts with cysteine sulfhydryl groups. In this study, we characterized HNE synaptosomal toxicity and evaluated the role of putative nucleophilic amino acid targets. Results show that HNE exposure of striatal synaptosomes inhibited 3H-dopamine membrane transport and vesicular storage. These concentration-dependent effects corresponded to parallel decreases in synaptosomal sulfhydryl content. Calculations of quantum mechanical parameters (softness, electrophilicity) that describe the interactions of an electrophile with its nucleophilic target indicated that the relative softness of HNE was directly related to both the second-order rate constant (k 2) for sulfhydryl adduct formation and corresponding neurotoxic potency (IC50). Computation of additional quantum mechanical parameters that reflect the relative propensity of a nucleophile to interact with a given electrophile (chemical potential, nucleophilicity) indicated that the sulfhydryl thiolate state was the HNE target. In support of this, we showed that the rate of adduct formation was related to pH and that N-acetyl-L-cysteine, but not N-acetyl-L-lysine or β-alanyl-L-histidine, reduced in vitro HNE neurotoxicity. These data suggest that, like other type 2 alkenes, HNE produces nerve terminal toxicity by forming adducts with sulfhydryl thiolates on proteins involved in neurotransmission.
Related Links	http://dx.doi.org/10.1093/toxsci/kfn226
Ending Page	181
Page Count	11
Starting Page	171
File Format	PDF
ISSN	10966080
e-ISSN	10960929
Journal	Toxicological Sciences
Issue Number	1
Volume Number	107
Language	English
Publisher	Oxford University Press
Publisher Date	2008-10-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Toxicology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Toxicology

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Synaptosomal Toxicity and Nucleophilic Targets of 4-Hydroxy-2-Nonenal

MOLECULAR MECHANISMS OF 4-HYDROXY-2-NONENAL AND ACROLEIN TOXICITY: NUCLEOPHILIC TARGETS AND ADDUCT FORMATION

Inhibition of Hsp72-Mediated Protein Refolding by 4-Hydroxy-2-nonenal

Protein targets for carbonylation by 4-hydroxy-2-nonenal in rat liver mitochondria

Modification and Functional Inhibition of Regulator of G-Protein Signaling 4 (RGS4) by 4-Hydroxy-2-nonenal

Formation of (2E)-4-Hydroxy-2-nonenal and (2E)-4-Hydroxy-2-hexenal by Plant Enzymes: A Review Suggests a Role in the Physiology of Plants

Formation of Deoxyguanosine Cross-links from Calf Thymus DNA Treated with Acrolein and 4-Hydroxy-2-nonenal

Pathways of 4-Hydroxy-2-Nonenal Detoxification in a Human Astrocytoma Cell Line

Ascorbic Acid Promotes Detoxification and Elimination of 4-Hydroxy-2(E)-nonenal in Human Monocytic THP-1 Cells

Synaptosomal Toxicity and Nucleophilic Targets of 4-Hydroxy-2-Nonenal

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