Possible structural and functional determinants contributing to the clastogenicity of pharmaceuticals

The battery of regulatory genotoxicity studies required in support of new drug registration has remained largely static since its inception some thirty years ago. The Ames mutagenicity assay still forms the foundation for this testing being highly reproducible and, for the most part, transparent. The same is not necessarily true of in vitro mammalian chromosome aberration assays since there is a fairly large and growing number of molecules without clear structural genotoxicity alerts (DEREK, MCASE), which are negative in Ames testing but positive in aberration studies, often only at high concentrations and/or cytotoxicity. Interpretation and risk assessment of these positive results can be problematic since there is no clear understanding of the process that generates them. The present paper builds on our previous observations suggesting that non covalent drug/DNA interactions, which are not adequately modeled in computational programs, may help explain some of these unexpected positive results. In particular, it is suggested that N-dimethyl groups and certain pyridine/piperidine aryl ketones may play a contributory role in genotoxicity, perhaps via DNA intercalation and topoisomerase inhibition. Clastogenicity arising from topoisomerase inhibition would be expected to be a threshold phenomenon and, as such, may carry a distinctly reduced risk relative to clastogenicity associated with covalent drug/DNA interactions.