Mechanisms of soft and hard electrophile toxicities

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Electron-deficient chemicals (electrophiles) react with compounds that have one or more unshared valence electron pairs (nucleophiles). The resulting covalent reactions between electrophiles and nucleophiles (e.g., Michael addition, S N 2 reactions) are important, not only to Organic Chemistry, but also to the fields of Molecular Biology and Toxicology. Specifically, covalent bond formation is the operational basis of many critically important cellular processes; e.g., enzyme function, neurotransmitter release, and membrane-vesicle fusion. Given this context it is understandable that these reactions are also relevant to Toxicology, since a significant number of xenobiotic chemicals are toxic electrophiles that can react with endogenous nucleophilic residues. Therefore, the purpose of this Review is to discuss electrophile-nucleophile chemistry as it pertains to cell injury and resulting organ toxicity. Our discussion will involve an introduction to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson. The HSAB concept provides a framework for calculation of quantum chemical parameters that classify the electrophile and nucleophile covalent components according to their respective electronic nature (softness/hardness) and reactivity (electrophilicity/nucleophilicity). The calculated quantum indices in conjunction with corroborative in vivo, in chemico (cell free) and in vitro research can offer an illuminating approach to mechanistic discovery. Accordingly, we will provide examples that demonstrate how this approach has been used to discern mechanisms and sites of electrophile action.

Original languageEnglish (US)
Pages (from-to)62-69
Number of pages8
JournalToxicology
Volume418
DOIs
StatePublished - Apr 15 2019

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Nucleophiles
Toxicology
Toxicity
Organic Chemistry
Electrons
Membrane Fusion
Acids
Poisons
Hardness
Xenobiotics
Neurotransmitter Agents
Molecular Biology
Molecular biology
Covalent bonds
Wounds and Injuries
Enzymes
Research
Fusion reactions
Membranes
In Vitro Techniques

Keywords

  • Electrophilic toxicants
  • Environmental pollution
  • Nucleophiles
  • Toxicity
  • type-2 alkenes
  • α,β-unsaturated aldehydes

ASJC Scopus subject areas

  • Toxicology

Cite this

Mechanisms of soft and hard electrophile toxicities. / LoPachin, Richard M.; Geohagen, Brian C.; Nordstroem, Larsulrik R.

In: Toxicology, Vol. 418, 15.04.2019, p. 62-69.

Research output: Contribution to journalReview article

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N2 - Electron-deficient chemicals (electrophiles) react with compounds that have one or more unshared valence electron pairs (nucleophiles). The resulting covalent reactions between electrophiles and nucleophiles (e.g., Michael addition, S N 2 reactions) are important, not only to Organic Chemistry, but also to the fields of Molecular Biology and Toxicology. Specifically, covalent bond formation is the operational basis of many critically important cellular processes; e.g., enzyme function, neurotransmitter release, and membrane-vesicle fusion. Given this context it is understandable that these reactions are also relevant to Toxicology, since a significant number of xenobiotic chemicals are toxic electrophiles that can react with endogenous nucleophilic residues. Therefore, the purpose of this Review is to discuss electrophile-nucleophile chemistry as it pertains to cell injury and resulting organ toxicity. Our discussion will involve an introduction to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson. The HSAB concept provides a framework for calculation of quantum chemical parameters that classify the electrophile and nucleophile covalent components according to their respective electronic nature (softness/hardness) and reactivity (electrophilicity/nucleophilicity). The calculated quantum indices in conjunction with corroborative in vivo, in chemico (cell free) and in vitro research can offer an illuminating approach to mechanistic discovery. Accordingly, we will provide examples that demonstrate how this approach has been used to discern mechanisms and sites of electrophile action.

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