title: Evidence for and role of the dimethylamino group in tamoxifen DNA intercalation in intact Chinese hamster V79 cells.
abstract: The in vitro and in vivo genotoxicity of tamoxifen is well documented but the underlying mechanism of this genotoxicity is only poorly understood. Tamoxifen is known to form adducts with DNA and it has been suggested that DNA intercalation may facilitate this covalent interaction. However, the low aqueous solubility of tamoxifen has made it difficult to demonstrate DNA intercalation by standard physico-chemical methods. In the present paper, we have employed the Chinese hamster V79 cell-based assay for the detection of DNA intercalation and report that tamoxifen, indeed, appears to have DNA intercalative properties. A partial structure activity relationship evaluation suggests that the N-dimethyl group of tamoxifen enhances intercalation.
authors.affiliation: Bristol-Myers Squibb Pharma Company, Newark, DE 19714, USA. ronald.snyder@spcorp.com
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Snyder
authors.forename: John E
authors.initials: JE
authors.lastname: Brown
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004965:Estrogen Antagonists / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004996:Ethidium / Q000737:chemistry / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D015162:Micronucleus Tests / Q000379:methods; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
chemical_list: D018736:DNA Adducts; D004338:Drug Combinations; D004965:Estrogen Antagonists; D007364:Intercalating Agents; D013629:Tamoxifen; D001761:Bleomycin; D004247:DNA; D004996:Ethidium