A review of the electrophilic reaction chemistry involved in covalent protein binding relevant to toxicity

Abstract

Several pieces of legislation have led to an increased interest in the use of in silico methods, specifically the formation of chemical categories for the assessment of toxicological endpoints. For a number of endpoints, this requires a detailed knowledge of the electrophilic reaction chemistry that governs the ability of an exogenous chemical to form a covalent adduct. Historically, this chemistry has been defined as compilations of structural alerts without documenting the associated electrophilic chemistry mechanisms. To address this, this article has reviewed the literature defining the structural alerts associated with covalent protein binding and detailed the associated electrophilic reaction chemistry. This information is useful to both toxicologists and regulators when using the chemical category approach to fill data gaps for endpoints involving covalent protein binding. The structural alerts and associated electrophilic reaction chemistry outlined in this review have been incorporated into the OECD (Q)SAR Toolbox, a freely available software tool designed to fill data gaps in a regulatory environment without the need for further animal testing.

Development of an in Silico Profiler for Mitochondrial Toxicity

“…When utilised together, multiple structural alerts pertaining to the same MIE form the basis of an in silico profiler. [13][14][15][16] The information within an in silico profiler can, in turn, be used to develop chemical categories centred on a common MIE (note that multiple MIEs can be initiated by a single chemical). This allows for read-across and data gap filling to be applied.…”

“…[10][11][16][17][18] A number of in silico profilers have been developed for a variety of organ-level toxicities, such as skin sensitisation, respiratory sensitisation, genotoxicityand hepatotoxicity. [13][14][15][19][20][21] However, very few profilers have dealt with toxicity induced by mitochondrial dysfunction. 1,22,23 This is, in part, due to the number of mechanisms by which a chemical could induce mitochondrial dysfunction 24 .…”

Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

“…An in-house KNIME Workflow was used to identify protein reactive compounds (Enoch et al 2011). Depending on the classification given by the KNIME Workflow, the organic compounds were assigned to each mode of action using a manual implementation of the Verhaar et al (1992) scheme.…”

“…Specifically acting chemicals exhibit toxicity due to (specific) interactions with certain receptor molecules (specific or receptor toxicity). A series of structural rules which aimed to classify compounds according to modes of toxic action have been reported historically in the literature (Hermens 1990;von der Ohe et al 2005;Enoch et al 2008Enoch et al , 2011 and were the basis of those defined by Verhaar et al (1992).…”

Application ofin silicoandin vitromethods in the development of adverse outcome pathway constructs in wildlife

“…the lack of an alert within a compound does not necessarily imply lack of toxicity). Reviews of alerts associated with covalent protein binding [8] and covalent DNA binding [9] have been published. Structural alerts associated with MIEs and the ability to elicit specific toxicities are continually being developed.…”