A REVIEW AND INVESTIGATION INTO THE MECHANISTIC BASIS OF THE GENOTOXICITY OF ANTIHISTAMINES

The genotoxicity of twenty one clinically used (or discontinued) antih istamines is reviewed. New results are also presented from an evaluati on of selected antihistamines in the V79 in vitro micronucleus assay. For two antihistamines, no genotoxicity data is available. Of the rema ining nineteen, nine have been reported as positive and one equivocal in at least one genotoxicity assay despite the fact that none possess structural alerts for genotoxicity. Ethidium displacement and bleomyci n amplification studies in V79 cells indicate that nine of these ten a ntihistamines are capable of intercalative DNA binding. Further, nine of the ten positive compounds, but none of the tested compounds which also intercalate but are reported to be negative in gene-tox assays (e .g. triprolidine, chlorcyclizine, clemastine), possess a dimethylamino substituent suggesting the requirement for this cationic function in the genotoxicity. It is proposed that the apparent genotoxicity of ant ihistamines and possibly many other pharmaceuticals derives from a hit herto unappreciated propensity of these drugs for stabilized intercala tive DNA binding. It is further proposed that the bleomycin amplificat ion assay may provide a widely applicable means for assessing function al intercalative drug/DNA interaction in intact mammalian cells. (C) 1 998 Elsevier Science B.V. All rights reserved.