Drug-induced mutagenesis typically involves the reaction of a drug or a drug-derived reactive intermediate with canonical DNA.  Errors in the replication or repair of covalently-modified DNA, in turn, lead to the introduction of mutations into the genetic code.  In the work described here we consider the possibility that mutagenic properties can arise via reaction of drugs with endogenous DNA lesions, rather than with canonical DNA.  Hydralazine is a clinically-used antihypertensive drug that displays both mutagenic and epigenetic properties.  We will report gel electrophoretic and mass spectrometric evidence that medicinally-relevant concentrations of hydralazine rapidly form covalent adducts with abasic sites in double-stranded and single-stranded DNA under physiological conditions.  Abasic sites are ubiquitous lesions in mammalian DNA and our results raise the intriguing possibility that the mutagenic properties of hydralazine could arise via formation of adducts with an endogenous DNA lesion, rather than via reaction with canonical DNA.

Generation of covalent DNA adducts via reaction of the antihypertensive drug hydralazine with abasic sites:  A new mechanism for drug-induced mutagenesis?

248th National Meeting (2014)

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