DNA adducts of propylene oxide and acrylonitrile epoxide: Hydrolytic deamination of 3-alkyl-dCyd to 3-Alkyl-dUrd

Abstract

Propylene oxide (PO) and acrylonitrile epoxide (ANO) are 3-carbon epoxides that are direct-acting mutagens. PO is a rodent carcinogen, and ANO has been postulated to be the ultimate carcinogenic form of acrylonitrile (AN). We have studied the reactions of these agents with 2'-deoxynucleosides and in vitro with calf thymus DNA at pH 7.0 to 7.5 and 37°C. PO was reacted with DNA for 10 hr and resulted in the formation of the following 2-hydroxypropyl (HP) adducts : N6-HP-dAdo (1 nmole/mg DNA), 3-HP-Ade (14 nmole/mg DNA), 7-HP-Gua (133 nmole/mg DNA) and 3-HP-dUrd (13 nmole/mg DNA). 3-HP-dUrd was formed after initial alkylation at N-3 of dCyd followed by conversion of the adjacent exocyclic imino group at C-4 to an oxygen (hydrolytic deamination) with the formation of a dUrd adduct. ANO was reacted for 3 hr with calf thymus DNA and yielded N6-(2-hydroxy-2-carboxyethyl-dAdo (N6-HOCE-dAdo)(2 nmole/mg DNA); 1, N6-ethene-dAdo (11 nmole/mg DNA); 7-(2-oxoethyl)-Gua (7-OXE-Gua)(110 nmole/DNA); 3-OXE-dThd (1 nmole/mg DNA); and 3-HOCE-dUrd (80 nmole/mg DNA). As with 3-HP-dUrd (80 nmole/mg DNA). As with 3-HP-dUrd, 3-HOCE-dUrd resulted from hydrolytic deamination of an initially formed dCyd adduct. A mechanism is proposed for the conversion of 3-alkyl-dCyd to 3-alkyl-dUrd involving intramolecular catalysis by the OH group on the 3-carbon side chain of the adduct. This cytosine to uracil conversion may be a common phenomenon with aliphatic epoxides and may play a role in the mutagenic and carcinogenic activity of this class of compounds.