Covalent adduct formation between the antihypertensive drug hydralazine and abasic sites in double and single-stranded DNA

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Hydralazine is an antihypertensive agent that displays both mutagenic and epigenetic properties. Here, we provide evidence that medicinally-relevant concentrations of hydralazine rapidly form covalent adducts with abasic sites in doublestranded and single-stranded DNA under physiologically-relevant conditions. We further probe the ability of other compounds to form covalent adducts with abasic sites and compare the rates to hydralazine. Finally, we initially assess the ability of adduct formed between hydralazine and abasic sites to block the base excision repair endonuclease APE I. The findings raise the intriguing possibility that the genotoxic properties of some compounds might arise via reactions with endogenous DNA lesions, rather than with the canonical structure of DNA.