Structures of the DNA adducts formed in mouse liver after administration of the proximate hepatocarcinogen 1'-hydroxyestragole.

作者：David H. Phillips, JAMES ALEXANDER MILLER, Elizabeth Clarke Miller, Bruce R. Adams · 发表于：PubMed · 年份：1981 · 被引用次数：113 · 研究领域：Cancer therapeutics and mechanisms、Plant Toxicity and Pharmacological Properties、Carbohydrate Chemistry and Synthesis

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 × 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 A...