Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant - Target interactions

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

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Many chemical toxicants and/or their active metabolites are electrophiles that cause cell injury by forming covalent bonds with nucleophilic targets on biological macro-molecules. Covalent reactions between nucleophilic and electrophilic reagents are, however, discriminatory since there is a significant degree of selectivity associated with these interactions. Over the course of the past few decades, the theory of Hard and Soft, Acids and Bases (HSAB) has proven to be a useful tool in predicting the outcome of such reactions. This concept utilizes the inherent electronic characteristic of polarizability to define, for example, reacting electrophiles and nucleophiles as either hard or soft. These HSAB definitions have been successfully applied to chemical-induced toxicity in biological systems. Thus, according to this principle, a toxic electrophile reacts preferentially with biological targets of similar hardness or softness. The soft/hard classification of a xenobiotic electrophile has obvious utility in discerning plausible biological targets and molecular mechanisms of toxicity. The purpose of this perspective is to discuss the HSAB theory of electrophiles and nucleophiles within a toxicological framework. In (Figure presented) principle, covalent bond formation can be described by using the properties of their outermost or frontier orbitals. Because these orbital energies for most chemicals can be calculated using quantum mechanical models, it is possible to quantify the relative softness (σ) or hardness (η) of electrophiles or nucleophiles and to subsequently convert this information into useful indices of reactivity. This atomic level information can provide insight into the design of corroborative laboratory research and thereby help investigators discern corresponding molecular sites and mechanisms of toxicant action. The use of HSAB parameters has also been instrumental in the development and identification of potential nucleophilic cytoprotectants that can scavenge toxic electrophiles. Clearly, the difficult task of delineating molecular sites and mechanisms of toxicant action can be facilitated by the application of this quantitative approach.

Original languageEnglish (US)
Pages (from-to)239-251
Number of pages13
JournalChemical Research in Toxicology
Volume25
Issue number2
DOIs
StatePublished - Feb 20 2012

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Nucleophiles
Acids
Covalent bonds
Poisons
Hardness
Toxicity
Xenobiotics
Biological systems
Research laboratories
Metabolites
Toxicology
Macros
Research Personnel
Molecules
Wounds and Injuries
Research

ASJC Scopus subject areas

  • Toxicology

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Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant - Target interactions. / LoPachin, Richard M.; Gavin, Terrence; DeCaprio, Anthony; Barber, David S.

In: Chemical Research in Toxicology, Vol. 25, No. 2, 20.02.2012, p. 239-251.

Research output: Contribution to journalArticle

LoPachin, Richard M. ; Gavin, Terrence ; DeCaprio, Anthony ; Barber, David S. / Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant - Target interactions. In: Chemical Research in Toxicology. 2012 ; Vol. 25, No. 2. pp. 239-251.
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