DNA intercalative potential of marketed drugs testing positive in in vitro cytogenetics assays

• Published in: Mutation research Vol. 609; no. 1; pp. 47 - 59
• Main Authors: Snyder, Ronald D., Ewing, Douglas, Hendry, Lawrence B.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.10.2006; Elsevier
• Subjects: Animals; Biological and medical sciences; Cell Line; Computer Simulation; DNA - chemistry; DNA - drug effects; DNA - genetics; DNA intercalation; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genotoxicity; Hydrogen Bonding; Intercalating Agents - administration & dosage; Intercalating Agents - chemistry; Intercalating Agents - toxicity; Marketed pharmaceuticals; Medical sciences; Micronuclei, Chromosome-Defective - chemically induced; Micronucleus Tests; Models, Chemical; Molecular Structure; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - chemistry; Product Surveillance, Postmarketing; Software; Static Electricity; Toxicology; DNA intercalation; Marketed pharmaceuticals; Genotoxicity; Drug; Toxicology; Toxicity; DNA; Cytogenetics; Genetics; In vitro
• ISSN: 1383-5718; 0027-5107; 1879-3592
• DOI: 10.1016/j.mrgentox.2006.06.001

We have previously noted that the Physicians’ Desk Reference (PDR) contains over 80 instances in which a drug elicited a positive genotoxic response in one or more in vitro assays, despite having no obvious structural features predictive of covalent drug/DNA interactive potential or known mechanistic basis. Furthermore, in most cases, these drugs were “missed” by computational genotoxicity-predicting models such as DEREK, MCASE and TOPKAT. We have previously reported the application of a V79 cell-based model and a 3D DNA docking model for predicting non-covalent chemical/DNA interactions. Those studies suggested that molecules that are very widely structurally diverse may be capable of intercalating into DNA. To determine whether such non-covalent drug/DNA interactions might be involved in unexpected drug genotoxicity, we evaluated, using both models where possible, 56 marketed pharmaceuticals, 40 of which were reported as being clastogenic in in vitro cytogenetics assays (chromosome aberrations/mouse lymphoma assay). As seen before, the two approaches showed good concordance (62%) and 26 of the 40 (65%) drugs exhibiting in vitro clastogenicity were predicted as intercalators by one or both methods. This finding provides support for the hypothesis that non-covalent DNA interaction may be a common mechanism of clastogenicity for many drugs having no obvious structural alerts for covalent DNA interaction.