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Further Characterization of the DNA Adducts Formed by Electrophilic Esters of the Hepatocarcinogens 1'-Hydroxysafrole and 1'-Hydroxyestragole in Vitro and in Mouse Liver in Vivo, Including New Adducts at C-8 and N-7 of Guanine Residues¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

The identities of the adducts formed on reaction of the model electrophilic and carcinogenic esters 1'-acetoxysafrole or 1'-acetoxyestragole with deoxyguanosine in vitro and those formed in vivo in the hepatic DNA of 12-day-old male C57BL/6 x C3H/He F₁ (hereafter called B6C3F₁) mice treated with 1'-hydroxysafrole or 1'-acetoxysafrole were investigated further with more discriminating high-performance liquid chromatgraphy systems than previously used. The adducts formed from the reactions of 1'-acetoxysafrole or 1'-acetoxyestragole are strictly analogous and are distinguished by the prefixes S and E, respectively. Five adducts, including S(E)-II identified by Phillips et al. (Cancer Res., 41: 176–186, 2664–2671, 1981) as N²-(trans-isosafrol-3'-yl)deoxyguanosine and the analogous isoestragole derivative, have been characterized from the reactions with each ester. Adducts S-I and E-I, tentatively identified by Phillips et al. as N²-(safrol-1'-yl)- or N²-(estragol-1'-yl)deoxyguanosine, were each resolved into a pair of diastereomers. The proposed structures for each diastereomer were confirmed by nuclear magnetic resonance and circular dichroism spectroscopy. Two new adducts, i.e., S(E)-V and S(E)-VI, were isolated from each reaction mixture. On the basis of their pK_as, their loss of ³H from [8-³H]deoxyguanosine, their retention of ³H from [1',2'-³H]deoxyguanosine, and their nuclear magnetic resonance spectra, Adducts S-V and E-V were characterized as 8-(trans-isosafrol-3'-yl)- and 8-(trans-isoestragol-3'-yl)deoxyguanosine, respectively. Adducts S-VI and E-VI were characterized in a similar manner as 7-(trans-isosafrol-3'-yl)- and 7-(trans-isoestragol-3'-yl)guanine, respectively. Adducts S-III and E-III, minor components described in the earlier studies, were not observed in the present work. High-performance liquid chromatography of hydrolysates of the hepatic DNA of male 12-day-old B6C3F₁ mice killed 9 h after a single dose (0.1 µmol/g body weight) of [2',3'-³H]-1'-hydroxysafrole showed that Adducts S-Ia, S-Ib, S-II, S-IV (identified by Phillips et al. as N⁶-(trans-isosafrol-3'-yl)deoxyadenosine), S-V, and S-VI were present at average levels of 3.5, 7.0, 24.4, 2.9, 1.2, and 3.6 pmol/mg DNA, respectively. Similar levels of these adducts were found in the hepatic DNA after administration of the same dose of [2',3'-³H]-1'-acetoxysafrole under identical conditions.

¹ This work was supported by Grants CA-07175, CA-22484, and CA-09135 of the National Cancer Institute, USPHS.

² Supported by a graduate fellowship awarded to James A. and Elizabeth C. Miller by the Upjohn Co., Kalamazoo, MI.

³ To whom requests for reprints should be addressed.

Received 1/11/85. Revised 4/ 2/85. Accepted 4/ 8/85.