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Structures of the DNA Adducts Formed in Mouse Liver after Administration of the Proximate Hepatocarcinogen 1'-Hydroxyestragole¹

McArdle Laboratory for Cancer Research, and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706

1'-Hydroxyestragole is a proximate carcinogenic metabolite of the naturally occurring hepatocarcinogen estragole (1-allyl-4-methoxybenzene). Two major (I and II) and 2 minor (III and IV) nucleoside adducts were found by high-performance liquid chromatography (HPLC) of enzymatic hydrolysates of hepatic DNA isolated from adult female CD-1 or preweanling C57BL/6 x C3H/He F₁ mice that had been given i.p. injections of 1'-[2',3'-³H]hydroxyestragole. Reaction of 1'-acetoxyestragole, a model electrophilic and mutagenic ester, with [¹⁴C]deoxyguanosine ([¹⁴C]dGuo) yielded products that coeluted on HPLC with Adducts I, II, and III, while Adduct IV coeluted with a product of the reaction of 1'-acetoxyestragole with [¹⁴C]deoxyadenosine. The in vivo adducts did not comigrate with any major reaction products of either 1'-hydroxyestragole-2',3'-oxide or 1'-oxoestragole with [¹⁴C]dGuo or [¹⁴C]deoxyadenosine. The pH partition coefficient patterns of the in vivo- and in vitro-derived dGuo Adducts I, II, and III together with the ³H:¹⁴C ratios of the three adducts from the reaction of 1'-acetoxyestragole with [8-¹⁴C,8-³H]dGuo indicated that each of these adducts contains a N²-substituted dGuo residue. Synthetic samples of Adducts II and IV were characterized from their nuclear magnetic resonance spectra and assigned the structures N²-(trans-isoestragol-3'-yl)deoxyguanosine and N²-(trans-isoestragol-3'-yl)deoxyadenosine, respectively. Hydrolysis at 100° with 0.1 N HCl for 30 min of the in vivo Adducts I and II yielded in each case radioactivity which coeluted on HPLC with 3'-hydroxyisoestragole. If Adduct I was first reduced with H₂:platinum and then hydrolyzed, radioactivity eluted with 1'-hydroxy-2',3'-dihydroestragole. Adduct I is therefore assigned the structure N²-(estragol-1'-yl)deoxyguanosine. Adduct III was converted in part to Adduct II on chromatography on HPLC and is thus tentatively regarded as N²-(cis-isoestragol-3'-yl)deoxyguanosine. All four adducts in the mouse liver can be accounted for by the reaction of a metabolically derived ester of 1'-hydroxyestragole with purine bases in DNA by S_N1, S_N2, or S_N2' mechanisms.

¹ This work was supported by Grants CA-07175 and CA-22484 from the National Cancer Institute, USPHS.

² Present address: Department of Biological Sciences, Stanford University, Stanford, Calif. 94305.

³ To whom requests for reprints should be addressed.

Received 8/ 9/80. Accepted 10/ 8/80.

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