Structure–activity relationships for thiol reactivity and rat or human hepatocyte toxicity induced by substituted p‐benzoquinone compounds

Abstract

Covalent binding of toxic chemicals to cellular targets is a molecular interaction that initiates a wide array of adverse biological effects. The creation of a covalent bond can be cited as a key initiating step along many toxicity pathways which must be predicted in order to predict the potential of a chemical to cause specific harmful effects. Currently, quantitative structure-activity relationship (QSAR) models are being improved by focusing on endpoints such as simple electrophile reactivity for covalent interactions rather than on commonly used complex toxicity endpoints. The cytotoxicity and electrophilic reactivity of 10 p-substituted benzoquinone derivatives, which are well known electrophilic alkylating agents, were investigated under the premise that QSAR toxicity models can be improved when the molecular triggering event is considered. Hepatocyte toxicity was determined by incubation of individual compounds with freshly isolated rat or cryopreserved human hepatocyte suspensions. The potential for chemical reactivity between a chemical and cellular target was measured by determining non-enzymic reactivity with glutathione, representing thiol nucleophiles. The decline in free thiol moieties was measured to characterize the electrophile reactivity. It was found that the degree of rat hepatotoxicity induced by benzoquinones correlated with the rate at which they non-enzymically react with glutathione and to various global and atomic electronic frontier orbital parameters which described electrophilicity. Human hepatocytes showed similar results but the statistical significance was much lower. The QSAR expressions suggest that covalent binding reactivity serves as a good correlate to hepatotoxicity and could improve QSAR modeling for potential toxicity risks.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…For example, Chan and coworkers have used linear regression analysis to develop several correlations between physicochemical parameters and hepatocyte toxicity of a few chemical classes: alpha,beta-unsaturated esters, α,β-unsaturated aldehydes, p-benzoquinones and halobenzenes (Chan et al, 2007(Chan et al, , 2008a. Such models are not directly useful in the regulatory assessment of chemicals, but they have helped to establish mechanisms of hepatotoxicity, and they have identified useful descriptors for further model development.…”

“…Human clinical hepatobiliary and renal tract toxicities pharmaceuticals ~1600 Roy et al (2008) rat hepatocyte toxicity phenols 31 Chan et al (2008a) human and rat hepatocyte toxicity p-benzoquinones 10 Chan et al (2008b) rat hepatocyte toxicity acrylates and methacrylates…”

Prediction of the Toxicity of Dimethylformamide, Methyl Ethyl Ketone, and Toluene Mixtures by QSAR Modeling

“…13,14 Quantitative-structure activity relationship (QSAR) analysis, which applies variables including physico-chemical properties and biological information to an equation to estimate and analyze toxicity, has been widely used to estimate the toxicity of materials. QSAR analysis has been used mainly in the fields of medicine, pharmacy, environmental science, toxicology, and biology as a way of predicting physico-chemical and biological properties via statistical models, and its use has gradually spread to other areas.…”

“…QSAR analysis has been used mainly in the fields of medicine, pharmacy, environmental science, toxicology, and biology as a way of predicting physico-chemical and biological properties via statistical models, and its use has gradually spread to other areas. 13,[16][17][18] Additionally, QSAR analyses are expected to be valued by national and international organizations from a chemical management perspective, in that toxicity estimates generated by QSAR are allowed in REACH (registration, evaluation, and authorization of chemicals). In particular, hazard estimations in the context of occupational health are needed.…”

The QSAR Modeling of Cytotoxicity on Anthraquinones

“…QSAR studies on cytotoxicity have given good results on small and homogeneous datasets. For instance Liao et al [2,3] or Chan et al [4] obtained models with good statistical quality (R 2 close to 0.9) for datasets ranging from 10 to 25 compounds. The main parameters used to model cytotoxicity have been for example water-octanol partition coefficient, which describes a compounds membrane permeability and molecular orbital energies that characterize reactivity [2,3,4].…”