Molecular Mechanisms of the Conjugated α,β-Unsaturated Carbonyl Derivatives: Relevance to Neurotoxicity and Neurodegenerative Diseases
- 13 December 2007
- journal article
- review article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 104 (2), 235-249
- https://doi.org/10.1093/toxsci/kfm301
Abstract
Conjugated alpha,beta-unsaturated carbonyl derivatives such acrylamide, 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 alpha,beta-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 because common nerve terminal proteins are targeted by alpha,beta-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.Keywords
This publication has 162 references indexed in Scilit:
- Identification of S-nitrosylation motifs by site-specific mapping of the S -nitrosocysteine proteome in human vascular smooth muscle cellsProceedings of the National Academy of Sciences, 2006
- Acrylonitrile potentiates hearing loss and cochlear damage induced by moderate noise exposure in ratsToxicology and Applied Pharmacology, 2005
- Pathways towards and away from Alzheimer's diseaseNature, 2004
- Selective Covalent Binding of Acrylonitrile to Cys 186 in Rat Liver Carbonic Anhydrase III In VivoChemical Research in Toxicology, 2003
- Protein‐Bound AcroleinJournal of Neurochemistry, 1999
- Interactions of α, β-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1Chemico-Biological Interactions, 1997
- Effects of acrylamide on cotransmission in perivascular sympathetic and sensory nervesJournal of the Autonomic Nervous System, 1994
- Acute acrylonitrile toxicity: Studies on the mechanism of the antidotal effect of d- and l-cysteine and their N-acetyl derivatives in the ratToxicology and Applied Pharmacology, 1990
- The effects of acetaldehyde and acrolein on blood pressure in guanethidine-pretreated hypertensive ratsToxicology and Applied Pharmacology, 1983
- Application of the Principle of Hard and Soft Acids and Bases to Organic ChemistryJournal of the American Chemical Society, 1967