Quantitative structure toxicity relationships for phenols in isolated rat hepatocytes

Quantitative structure toxicity relationship (QSTR) equations were obtained to predict and describe the cytotoxicity of 31 phenols using log LD(50) as a concentration to induce 50% cytotoxicity of isolated rat hepatocytes in 2 h and log P as octanol/water partitioning: log LD(50) muM) = -0.588( +/-0.059)log P+4.652( +/-0.153) (n = 27, r(2) = 0.801, s = 0.261, P < 1 x 10(-9)). Hydroquinone, catechol, 4-nitrophenol, and 2,4-dinitrophenol were outliers for this equation. When the ionization constant pK(a) was considered as a contributing factor a two-parameter QSTR equation was derived: log LD50 (muM) = -0.595(+/-0.051)log P + 0.197(+/-0.029)pK(a) + 2.665( 0.281) (n = 28, r(2) = 0.859, s = 0.218, P < 1 X 10(-6)). Using sigma(+), the Brown variation of the Hammet electronic constant, as a contributing parameter, the cytotoxicity of phenols towards hepatocytes were defined by log LD(50) (muM) = -0.594(+/-0.052)log P - 0.552(+/-0.085)sigma(+) + 4.540(+/-0.132) (n = 28, r(2) = 0.853, s = 0.223, P < 1 x 10(-6)). Replacing sigma(+) with the homolytic bond dissociation energy (BDE) for (XPhOH+PhO*-X-PhO'+PhOH) led to log LD(50) (muM)=-0.601(+/-0.066)log P-0.040(+/-0.018)BDE + 4.611(+/- 0.166) (n = 23, r(2) = 0.827, s = 0.223, P < 0.05). Hydroquinone, catechol and 2-nitrophenol were outliers for the above equations. Using redox potential and log P led to a new correlation: log LD(50) (muM) = -0.529(+/-0.135)log P + 2.077( 0.892)E(p/2) +2.806(+/-0.592) (n= 15, r(2) = 0.561, s = 0.383, P < 0.05) with 4-nitrophenol as an outlier. Our findings indicate that phenols with higher lipophilicity, BDE, or sigma(+) values or with lower pKa and redox potential were more toxic towards hepatocytes. We also showed that a collapse of hepatocyte mitochondrial membrane potential preceded the cytotoxicity of most phenols. Our study indicates that one or a combination of mechanisms; i.e. mitochondrial uncoupling, phenoxy radicals, or phenol metabolism to quinone methides and quinones, contribute to phenol cytotoxicity towards hepatocytes depending on the phenol chemical structure. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.