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.
Hansch
C
C
Department of Chemistry, Pomona College, Claremont, CA, USA.
McKarns
S C
SC
Smith
C J
CJ
Doolittle
D J
DJ
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D004847:Epithelial Cells / Q000648:ultrastructure; D005609:Free Radicals; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000648:ultrastructure; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005609:Free Radicals; D010636:Phenols; D017382:Reactive Oxygen Species; C042329:phenoxy radical; D007770:L-Lactate Dehydrogenase