ToxSci Advance Access published online on December 13, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm301
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MOLECULAR MECHANISMS OF THE CONJUGATED 
,β–UNSATURATED CARBONYL DERIVATIVES: RELEVANCE TO NEUROTOXICITY AND NEURODEGENERATIVE DISEASES
* Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx NY 10467-2490
Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611-0885
Department of Chemistry, Iona College, New Rochelle, NY
Send Correspondence to: Richard M. LoPachin, Ph.D., Montefiore Medical Center, Moses Research Tower – 7, 111 E. 210th St. , Bronx, NY 10467-2490, (718) 920-5054 (phone), (718) 515-4903 (fax), lopachin{at}aecom.yu.edu. (e-mail)
Received October 3, 2007; revision received December 4, 2007; accepted December 4, 2007
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Abstract |
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Conjugated 
,β-unsaturated carbonyl derivatives such acrylamide (ACR), acrolein and 4-hydroxy-2-nonenal (HNE) are members of a large class of chemicals known as the type-2 alkenes. Human exposure through diet, occupation and pollution is pervasive and has been linked to toxicity in most major organs. Evidence suggests that these soft electrophiles produce toxicity by a common mechanism involving the formation of Michael-type adducts with nucleophilic sulfhydryl groups. In this commentary, the adduct chemistry of the ,β-unsaturated carbonyls and possible protein targets will be reviewed. We also consider how differences in electrophilic reactivity among the type-2 alkenes impact corresponding toxicokinetics and toxicological expression. Whereas these concepts have mechanistic implications for the general toxicity of type-2 alkenes, this commentary will focus on the ability of these chemicals to produce presynaptic damage via protein adduct formation. Given the ubiquitous environmental presence of the conjugated alkenes, discussions of molecular mechanisms and possible neurotoxicological risks could be important. Understanding the neurotoxicodynamic of the type-2 alkenes might also provide mechanistic insight into neurodegenerative conditions where neuronal oxidative stress and presynaptic dysfunction are presumed initiating events. This is particularly germane to a recent proposal that lipid peroxidation and the subsequent liberation of acrolein and HNE in oxidatively stressed neurons mediate synaptotoxicity in brains of Alzheimer's disease patients. This endogenous neuropathogenic process could be accelerated by environmental type-2 alkene exposure since common nerve terminal proteins are targeted by ,β-unsaturated carbonyl derivatives. Thus, the protein adduct chemistry of the conjugated type-2 alkenes offers a mechanistic explanation for the environmental toxicity induced by these chemicals and might provide insight into the pathogenesis of certain human neurodegenerative diseases.
Key Words: acrylamide; acrolein; Alzheimer's disease; 4-hydroxy-2-nonenal; synaptotoxicity; neurodegeneration.
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