DNA adducts of propylene oxide and acrylonitrile epoxide: hydrolytic deamination of 3-alkyl-dCyd to 3-alkyl-dUrd.
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 degrees 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-etheno-dAdo (11 nmole/mg DNA); 7-(2-oxoethyl)-Gua (7-OXE-Gua) (110 nmole/mg DNA); 3-OXE-dThd (1 nmole/mg DNA); and 3-HOCE-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Institute of Environmental Medicine, New York University Medical Center, NY 10016.
J J
JJ
Solomon
A
A
Segal
D000181:Acrylonitrile; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D003641:Deamination; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D005027:Ethylene Oxide / Q000031:analogs & derivatives* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D009570:Nitriles / Q000378:metabolism*
D002273:Carcinogens; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D009570:Nitriles; C033154:2-cyanoethylene oxide; D003841:Deoxycytidine; D004247:DNA; D005027:Ethylene Oxide; D000181:Acrylonitrile; D003857:Deoxyuridine; C009068:propylene oxide