||Quantitative Structure-Toxicity Relationships for a Series of Primary Alcohols in a Mammalian Viral Host Cell Reactivation Assay.
Benane, S. G. ;
Richard, A. M. ;
Blackman, C. F. ;
Lytle, C. D. ;
||Health Effects Research Lab., Research Triangle Park, NC. ;Food and Drug Administration, Rockville, MD. Center for Devices and Radiological Health.
Structure-activity relationships ;
DNA repair ;
Plaque assay ;
Cell survival ;
DNA damage ;
Ultraviolet rays ;
Host cell reactivation assay
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Structure-toxicity relationships for alcohols in a wide variety of systems have been found to depend primarily on the effective molar concentration of alcohol that penetrates to a lipid site of action in the cell, and not on specific structural features. In contrast, a structure-activity sutoff based on alcohol chain length has been reported for permeability of bacterial membranes. In the present study, structure-toxicity relationships for inhibition of DNA repair in mammalian cells were investigated for 16 aliphatic alcohols using a monkey kidney fibroblast - herpes simplex virus (HSV) assay. Ethanol had been studied previously and found to ihibit repair of damaged DNA. Cell toxicity and DNA repair inhibition were determined by adding individual alcohols to cell monolayers infected with intact HSV or UV-damaged HSV (UV-HSV), respectively, and measuring reduction in viral plaque formation. Log-log plots of 1/(alcohol concentrations yielding 20% reduction inHSV plaque formation or 50% inhibition of UV-HSV survival) versus log(octanol/water partition coefficients) yielded highly significant correlations (R squared=0.98) in each case. These quantitative structure-activity relationships imply similar rate limiting steps and are consistent with a baseline molar toxicity model that further validates the HSV repair inhibition assay for toxicity investigations.