Correlation between Hydrophobicity of Short-Chain Aliphatic Alcohols and Their Ability to Alter Plasma Membrane Integrity

The quantitative relationship between chemical structure andbiological activity has received considerable attention in thefields of pharmacology and drug development More recently, quantitativestructure-activity relationships (QSARs) have been used forpredicting chemical toxicity. It has been proposed that alcoholsmay elicit their toxic effects through hydrophobic interactionswith the cellular membrane. The objective of this study wasto evaluate the role of hydrophobicity in the loss of membraneintegrity following acute exposure to short-chain aliphaticalcohols in rat liver epithelial cellsin vitro. The series ofalcohols studied included methanol, ethanol, 1-propanol, 1-butanol,1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 2-butanol, 2-methyl-1-propanol,and 2-methyl-2-propanol. The lactate dehydrogenase (LDH) assaywas used to quantify membrane integrity. The logarithm of theoctanol/ water partition coefficient (log P) was used to quantifyhydrophobicity. LDH50 values, representing alcohol concentrationsyielding a 50% increase in LDH release relative to untreatedcontrols (i.e., mild disruption of membrane integrity), andEC50 values, representing alcohol concentrations yielding 50%of the maximal release of LDH (i.e., moderate disruption ofLDH release), were experimentally determined for each alcohol.The LDH50 and EC50 values were then used to derive the QSARrelationship. The aqueous alcohol concentrations yielding LDH50or EC50 values ranged from 8.9 x 10^–4M (LDH50 for octanol)to 3.5 m (EC50 for methanol), and the log P of the alcoholsranged from –0.77 (methanol) to 3.00 (octanol). From thesedata, we have derived two QSAR equations describing the roleof hydrophobicity in the release of LDH from rat liver epithelialcells following a 1-hr alcohol exposure. The QSAR equation forLDH50 values, log (1/LDH50) = 0.896 log P + 0.117 (n = 11, SD= 0.131), was nearly identical to the QSAR equation for EC50values, log (1/EC50) = 0.893 log P + 0.101 (n = 11, SD = 0.133],suggesting that similar structure-activity relationships existat both mild and moderate levels of membrane disruption. Ourdata indicate that an increase in LDH release was positivelyand linearly correlated with the hydrophobicity (r = 0.993).These data may help predict the potential biological effectsof other, as yet untested, aliphatic alcohols and aliphaticalcohol-like compounds (e.g., anesthetics) on the plasma membrane.