Direct alkylation of calf thymus DNA by acrylonitrile. Isolation of cyanoethyl adducts of guanine and thymine and carboxyethyl adducts of adenine and cytosine.
Reaction of the rodent carcinogen acrylonitrile (AN) at pH 7.0 for 10 and/or 40 days with 2'-deoxyadenosine (dAdo), 2'-deoxycytidine (dCyd), 2'-deoxyguanosine (dGuo), 2'-deoxyinosine (dIno), and thymidine (dThd) resulted in the formation of cyanoethyl and carboxyethyl adducts. The adducts isolated were 1-(2-carboxyethyl)-dAdo (1-CE-dAdo), N6-CE-dAdo, 3-CE-dCyd, 7-(2-cyanoethyl)-Gua (7-CNE-Gua), 7,9-bis-CNE-Gua, imidazole ring-opened 7,9-bis-CNE-Gua, 1-CNE-dIno, and 3-CNE-dThd. Structures were assigned on the basis of UV spectra and electron impact (EI), desorption chemical ionization (DCI) and Californium-252 fission fragment ionization mass spectra. The carboxyethyl adducts resulted from initial cyanoethylation at a ring nitrogen adjacent to an exocyclic nitrogen followed by rapid hydrolysis of the nitrile moiety to a carboxylic acid. It was postulated that the facile hydrolysis is the result of an intramolecular-catalyzed reaction resulting from the formation of a transient cyclic intermediate between nitrile carbon and exocyclic nitrogen. AN was reacted with calf thymus DNA (pH 7.0, 37 degrees C, 40 days) and the relative amounts of adducts isolated was 1-CE-Ade (25.8%), N6-CE-Ade (7.6%), 3-CE-Cyt (1.3%), 7-CNE-Gua (25.8%), 7,9-bis-CNE-Gua (4.3%), imidazole ring-opened 7,9-bis-CNE-Gua (18.9%) and 3-CNE-Thy (16.3%). Thus a carcinogen once adducted to a base in DNA was shown to be subsequently modified resulting in a mixed pattern of cyanoethylated and carboxyethylated AN-DNA adducts.(ABSTRACT TRUNCATED AT 250 WORDS)
D000181:Acrylonitrile / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000302:isolation & purification; D000478:Alkylation; D000818:Animals; D002417:Cattle; D003596:Cytosine / Q000031:analogs & derivatives / Q000302:isolation & purification; D004247:DNA / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000302:isolation & purification; D013058:Mass Spectrometry; D009570:Nitriles / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives / Q000302:isolation & purification; D013950:Thymus Gland
D009570:Nitriles; C047692:7-(2-cyanoethyl)guanine; C030326:3-(2-carboxyethyl)cytosine; D006147:Guanine; C026369:1-(2-carboxyethyl)adenine; C047693:3-(2-cyanoethyl)thymidine; D003596:Cytosine; D004247:DNA; D000225:Adenine; D000181:Acrylonitrile; D013936:Thymidine