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 residues.
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 chromatography 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 pKas, 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 mumol/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.
D000818:Animals; D000840:Anisoles / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004149:Dioxoles / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012451:Safrole / Q000031:analogs & derivatives / Q000378:metabolism*
D000840:Anisoles; D002273:Carcinogens; D004149:Dioxoles; C035922:1'-acetoxysafrole; C014037:1'-hydroxyestragole; D006147:Guanine; C035921:1'-acetoxyestragole; D004247:DNA; C012376:1'-hydroxysafrole; D012451:Safrole