Comparative QSAR evidence for a free-radical mechanism of phenol-induced toxicity

Phenol and 14 substituted-phenols were tested for their ability to impair epithelial cell membrane integrity in WB rat liver cells as determined by an increase in lactate dehydrogenase release. Two quantitative structure-activity relationship (QSAR) regression equations were developed which showed that separate mechanisms of phenolic cytotoxicity are important - nonspecific toxicity due to hydrophobicity and formation of phenoxyl radicals. The equations most predictive of phenol toxicity are denoted as log1/C=-0. 98sigma(+)+0.77logP+0.23 or log1/C=-0.11BDE+0.76logP+0.21, respectively, where C is the minimum concentration of substituted-phenol required for a toxic response. P is the octanol-water partition coefficient, sigma(+) is the electronic Hammett parameter and BDE is the OH homolytic bond dissociation energy. In the literature, phenol toxicity correlated to sigma(+) is rare, but there is strong evidence that phenols possessing electron-releasing groups may be converted to toxic phenoxyl radicals. A common feature in a variety of cells is generation of elevated amounts of reactive oxygen species (ROS) associated with a rapid growth rate. The slightly elevated cancer risk associated with the use of Premarin may be due to phenoxyl-type radicals derived from one or more of its components.