Molecular mechanisms of the conjugated α,β-unsaturated carbonyl derivatives

Relevance to neurotoxicity and neurodegenerative diseases

Richard M. LoPachin, David S. Barber, Terrence Gavin

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Conjugated α,β-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 α,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 because common nerve terminal proteins are targeted by α,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.

Original languageEnglish (US)
Pages (from-to)235-249
Number of pages15
JournalToxicological Sciences
Volume104
Issue number2
DOIs
StatePublished - Aug 2008

Fingerprint

Neurodegenerative diseases
Alkenes
Neurodegenerative Diseases
Derivatives
Toxicity
Acrolein
Proteins
Aptitude
Oxidative stress
Acrylamide
Brain Diseases
Nutrition
Occupations
Toxicology
Lipid Peroxidation
Neurons
Brain
Alzheimer Disease
Oxidative Stress
Pollution

Keywords

  • 4-hydroxy-2-nonenal
  • Acrolein
  • Acrylamide
  • Alzheimer's disease
  • Neurodegeneration
  • Synaptotoxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

Molecular mechanisms of the conjugated α,β-unsaturated carbonyl derivatives : Relevance to neurotoxicity and neurodegenerative diseases. / LoPachin, Richard M.; Barber, David S.; Gavin, Terrence.

In: Toxicological Sciences, Vol. 104, No. 2, 08.2008, p. 235-249.

Research output: Contribution to journalArticle

@article{98205ba58ad44c778d7a2a0e1e6255d0,
title = "Molecular mechanisms of the conjugated α,β-unsaturated carbonyl derivatives: Relevance to neurotoxicity and neurodegenerative diseases",
abstract = "Conjugated α,β-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 α,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 because common nerve terminal proteins are targeted by α,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.",
keywords = "4-hydroxy-2-nonenal, Acrolein, Acrylamide, Alzheimer's disease, Neurodegeneration, Synaptotoxicity",
author = "LoPachin, {Richard M.} and Barber, {David S.} and Terrence Gavin",
year = "2008",
month = "8",
doi = "10.1093/toxsci/kfm301",
language = "English (US)",
volume = "104",
pages = "235--249",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Molecular mechanisms of the conjugated α,β-unsaturated carbonyl derivatives

T2 - Relevance to neurotoxicity and neurodegenerative diseases

AU - LoPachin, Richard M.

AU - Barber, David S.

AU - Gavin, Terrence

PY - 2008/8

Y1 - 2008/8

N2 - Conjugated α,β-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 α,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 because common nerve terminal proteins are targeted by α,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.

AB - Conjugated α,β-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 α,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 because common nerve terminal proteins are targeted by α,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.

KW - 4-hydroxy-2-nonenal

KW - Acrolein

KW - Acrylamide

KW - Alzheimer's disease

KW - Neurodegeneration

KW - Synaptotoxicity

UR - http://www.scopus.com/inward/record.url?scp=42149161725&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42149161725&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfm301

DO - 10.1093/toxsci/kfm301

M3 - Article

VL - 104

SP - 235

EP - 249

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 2

ER -