Studies of the Mechanisms of Adduction of 2‘-Deoxyadenosine with Styrene Oxide and Polycyclic Aromatic Hydrocarbon Dihydrodiol Epoxides

• Published in: Chemical research in toxicology Vol. 13; no. 7; pp. 625 - 637
• Main Authors: Kim, Hye-Young H, Finneman, Jari I, Harris, Constance M, Harris, Thomas M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-07-2000
• Subjects: 2'-Deoxyadenosine; Base Sequence; Carcinogens - chemistry; Deoxyadenosines - chemistry; DNA Adducts - analysis; DNA Adducts - chemistry; Epoxy Compounds - chemistry; Magnetic Resonance Spectroscopy; Nitrogen Isotopes - analysis; Oligonucleotides - chemistry; Phenanthrenes - chemistry; styrene oxide
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx000054m

The mechanism of adduction of 2‘-deoxyadenosine by styrene oxide and polycyclic aromatic hydrocarbon dihydrodiol epoxides has been explored using 15N6-labeled adenine nucleosides. The extent of reaction at N1 versus N6 was evaluated by 1H NMR of the N6 adducts after allowing Dimroth rearrangement to occur. Products arising from attack at N1 followed by Dimroth rearrangement exhibited a small two-bond 1H−15N coupling constant (N1−H2 J ∼ 13 Hz); products from direct attack exhibited a much larger one-bond 1H−15N coupling constant (J ∼ 90 Hz). In the case of styrene oxide, all of the N6 β adduct arose by initial attack at N1, whereas the majority (70−80%) of the N6 α adducts came from direct attack. The styrene oxide reaction was also studied with a self-complementary oligodeoxynucleotide (24-mer) containing nine 15N6-labeled adenine residues. NMR examination of the N6 α- and β-styrene oxide adducts isolated after enzymatic degradation of the 24-mer gave very similar results, indicating that N1 attack can occur readily even with a duplexed oligonucleotide. With the PAH dihydrodiol epoxides, only naphthalene dihydrodiol epoxide exhibited significant initial reaction at N1 (50%). No detectable rearranged product was seen in reactions with benzo[a]pyrene dihydrodiol epoxide or non-bay or bay region benz[a]anthracene dihydrodiol epoxide; interestingly, a small amount of N1 attack (5−7%) was seen in the case of benzo[c]phenanthrene dihydrodiol epoxide. It appears that initial attack at N1 is only a significant reaction pathway for epoxides attached to a single aromatic ring.