Reactions of propylene oxide with 2'-deoxynucleosides and in vitro with calf thymus DNA

Propylene oxide (PO) is a direct-acting mutagen and rodent carcinogen. We have studied how PO modifies 2'-deoxynucleosides at pH 7.0-7.5 and 37 degrees C for 10 h. PO reacts as an SN2 alkylating agent by forming the following 2-hydroxypropyl (HP) adducts: N6-HP-dAdo (7% yield), 7-HP-Gua (37%) and 3-HP-dThd (4%). Alkylation at N-3 of dCyd resulted in conversion of the adjacent exocyclic imino group at C-4 to an oxygen (hydrolytic deamination) with the formation of a dUrd adduct, 3-HP-dUrd (14%). Ultraviolet spectroscopy and mass spectrometry were used for the structural determination of these adducts. Confirmation of the unexpected 3-HP-dUrd adduct was provided by an accurate mass measurement technique where diagnostic ions in the mass spectra of 3-HP-dUrd were measured to within 0.0005 atomic mass units of the predicted mass. PO was reacted in vitro with calf thymus DNA (pH 7.0-7.5, 37 degrees C, 10 h) and yielded N6-HP-dAdo (1 nmol/mg DNA), 3-HP-Ade (14 nmol/mg DNA), 7-HP-Gua (133 nmol/mg DNA) and 3-HP-dUrd (13 nmol/mg DNA). A mechanism for the hydrolytic deamination of 3-HP-dCyd to 3-HP-dUrd involving the OH on the HP side chain is proposed. This cytosine to uracil conversion may play a role in the mutagenic and carcinogenic activity of this epoxide.