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Stereoselective Formation of in Vitro Nucleic Acid Adducts by 2,3-Epoxy-4-hydroxynonanal¹

Section of Nucleic Acid Chemistry, Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595

This paper describes the reactions of purine nucleosides and nucleic acids with 2,3-epoxy-4-hydroxynonanal. 2,3-Epoxy-4-hydroxynonanal was produced with tert-butyl hydroperoxide by epoxidation of trans-4-hydroxy-2-nonenal, a lipid peroxidation product. The epoxy aldehyde exists as a pair of diastereomers, I and II. Because these isomers could not be completely separated under the chromatographic conditions used, reactions were carried out with a mixture of known proportions of isomers I and II. Reaction of adenine nucleosides with the epoxy aldehyde yielded diastereomers A1 and A2, which structures were assigned on the basis of their spectroscopic data and by chemical synthesis as 1,N⁶-etheno adducts possessing a heptyl group at C8. These adducts were formed from isomers I and II in a stereoselective manner. Isomer I appeared to be responsible for the formation of A2, whereas isomer II favored the production of A1. Stereoselectivity of isomers I and II was also observed upon reaction with guanine nucleosides in the formation of adducts G1, G2, G3, G4, G5, and G6. G2, G3, G5, and G6 were unstable in base and could be converted quantitatively to G1. The structures of these adducts were reported (Sodum, R. S., and Chung, F-L. Chem. Res. Toxicol., 2: 23–28, 1989). G5 and G6 were the products formed predominantly from reactions in which isomer I was in excess, whereas G1 and G4 were the major products in reactions enriched with isomer II. Incubation of DNA with the epoxy aldehyde at 37° and pH 7.0 yielded a modified DNA containing 1,N²-ethenodeoxyguanosine (G1) at levels of 10 pmol/mg DNA. Although G2, G3, G5, and G6 were not readily detected in this DNA hydrolysate, base conversion of fractions corresponding to these adducts to G1 indicated that the total yield of these adducts was equivalent to approximately 20% of that of G1. A1 and A2 were not found in this DNA. Contrary to the reactions with native DNA, reactions of single-stranded DNA resulted in the formation of primarily A1 and A2, with a total adduct level of 30 nmol/mg DNA. In this DNA, the yield of guanine adducts was relatively small, estimated at 0.73 nmol/mg DNA based on conversion to G1. RNA was extensively modified by the epoxy aldehyde, yielding both adenine and guanine nucleosides. The levels of adenine nucleoside adducts formed in RNA were greater than 50 nmol/mg RNA. The yields of guanine nucleoside adducts were 7.0 and 50 nmol/mg RNA depending on the proportion of isomers I and II in the reaction. Although isomer II showed a comparable reactivity for adenine and guanine nucleosides in RNA, isomer I seemed to be more reactive toward adenine than toward guanine, yielding levels of adenine adducts at least 7-fold greater than those of guanine adducts. Stereoselectivity of isomers I and II similar to that observed with monomers was also demonstrated with nucleic acids.

¹ This study was supported by Grant CA-43159 from the National Cancer Institute.

² To whom all correspondence should be addressed, at Division of Chemical Carcinogenesis, American Health Foundation, 1 Dana Road, Valhalla, NY 10595.

Received 5/ 8/90. Accepted 9/26/90.

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