CORRELATION BETWEEN HYDROPHOBICITY OF SHORT-CHAIN ALIPHATIC-ALCOHOLS AND THEIR ABILITY TO ALTER PLASMA-MEMBRANE INTEGRITY

The quantitative relationship between chemical structure and biologica l activity has received considerable attention in the fields of pharma cology and drug development. More recently, quantitative structure-act ivity relationships (QSARs) have been used for predicting chemical tox icity. It has been proposed that alcohols may elicit their toxic effec ts through hydrophobic interactions with the cellular membrane. The ob jective of this study was to evaluate the role of hydrophobicity in th e loss of membrane integrity following acute exposure to short-chain a liphatic alcohols in rat liver epithelial cells in vitro. The series o f alcohols studied included methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 2-butanol, 2-methyl-1-pr opanol, and 2-methyl-2-propanol. The lactate dehydrogenase (LDH) assay was used to quantify membrane integrity. The logarithm of the octanol / water partition coefficient (log P) was used to quantify hydrophobic ity. LDH50 values, representing alcohol concentrations yielding a 50% increase in LDH release relative to untreated controls (i.e., mild dis ruption of membrane integrity), and EC50 values, representing alcohol concentrations yielding 50% of the maximal release of LDH (i.e., moder ate disruption of LDH release), were experimentally determined for eac h alcohol. The LDH50 and EC50 values were then used to derive the QSAR relationship. The aqueous alcohol concentrations yielding LDH50 or EC 50 values ranged from 8.9 x 10(-4) M (LDH50 for octanol) to 3.5 M (EC5 0 for methanol), and the log P of the alcohols ranged from -0.77 (meth anol) to 3.00 (octanol). From these data, we have derived two QSAR equ ations describing the role of hydrophobicity in the release of LDH fro m rat liver epithelial cells following a 1-hr alcohol exposure. The QS AR equation for LDH50 values, log (1/LDH50) = 0.896 log P + 0.117 (n = 11, SD = 0.131), was nearly identical to the QSAR equation for EC50 v alues, log (1/EC50) = 0.893 log P + 0.101 (n = 11, SD = 0.133], sugges ting that similar structure-activity relationships exist at both mild and moderate levels of membrane disruption. Our data indicate that an increase in LDH release was positively and linearly correlated with th e hydrophobicity (r = 0.993). These data may help predict the potentia l biological effects of other, as yet untested, aliphatic alcohols and aliphatic alcohol-like compounds (e.g., anesthetics) on the plasma me mbrane. (C) 1997 Society of Toxicology.