Understanding the toxicity of phenols: Using quantitative structure-activity relationship and enthalpy changes to discriminate between possible mechanisms
Experimental studies of the "extended toxicity" of substituted phenols are mainly of two types: the toxicity due to phenoxyl radical formation and the toxicity caused by metabolites, for example, the formation of quinones. Quantitative structure-activity relationship (QSAR) studies of phenol toxicity have dealt with the formation of phenoxyl radicals using bond dissociation enthalpy (BDE) of parent phenols, have obtained good correlations with experimental data, and have concluded that phenoxyl radicals are the toxic agent. However, the actual toxic mechanism has remained poorly defined. In this study, we follow the metabolic pathways of monosubstituted phenols to their quinone end products and calculate enthalpy changes for all relevant reactions. These enthalpy changes are first used as descriptors for a QSAR analysis. Many of these new descriptors, including some relevant to quinone formation, are highly correlated with the BDE values of the parent phenols. Therefore, a QSAR analysis by itself is inconclusive as to the mechanism of toxicity. To better define the problem, we have returned to a detailed analysis of net enthalpy changes. We show that the formation of phenoxyl radical is the rate-determining step: This step is slow for electron-withdrawing group substituted phenols (EWG-phenols), whereas it is fast for electron-donating group substituted phenols (EDG-phenols). The study of net enthalpy changes of reactions reveals that once the phenoxyl radical is present, the corresponding quinone is rapidly formed, so that quinone formation may be ultimately responsible for toxicity of EDG-phenols. We then demonstrate how the suggested mechanism (quinone formation) is successful in predicting the toxicity of some complex phenols, which are predicted poorly using the phenoxyl radical argument. We also discuss the toxicities of some estrogens in light of the quinone mechanism.
|Journal||Chemical Research in Toxicology|
Shadnia, H. (Hooman), & Wright, J.S. (2008). Understanding the toxicity of phenols: Using quantitative structure-activity relationship and enthalpy changes to discriminate between possible mechanisms. Chemical Research in Toxicology, 21(6), 1197–1204. doi:10.1021/tx800058r