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ToxSci Advance Access published online on November 7, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn226
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.
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SYNAPTOSOMAL TOXICITY AND NUCLEOPHILIC TARGETS OF 4-HYDROXY-2-NONENAL

Richard M. LoPachin1, Brian C. Geohagen1 and Terrence Gavin2

1 Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th st., Bronx, NY 10467 2 Department of Chemistry, Iona College, New Rochelle, NY 10804

Corresponding author: Richard M. LoPachin, Ph.D., Montefiore Medical Center, Moses Research Tower – 7, 111 E. 210th St., Bronx, NY 10467. (718) 920-5054 (telephone), (718) 515-4903 (fax). lopachin{at}aecom.yu.edu (e-mail)

Received October 2, 2008; revision received October 2, 2008; accepted October 15, 2008


  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's 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 (k2) 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.

Key Words: {alpha},β-unsaturated carbonyl; nerve terminal toxicity; Alzheimer's disease; acrolein; oxidative stress.


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