Phillips D H, Miller J A, Miller E C, Adams B
Cancer Res. 1981 Jul;41(7):2664-71.
Administration of 1'-[2'-3'-3H]hydroxysafrole to adult female mice resulted in the formation of DNA-, ribosomal RNA-, and protein-bound adducts in the liver that reached maximum levels within 24 hr. The levels of all three macromolecule-bound adducts decreased rapidly between 1 and 3 days after injection, at which time the amounts of the DNA-bound adducts essentially plateaued at approximately 15% of the maximum level. The amounts of the protein and ribosomal RNA adducts were very low by 20 days. Comparison by high-performance liquid chromatography of the deoxyribonucleoside adducts obtained from the hepatic DNA with those formed by reaction of deoxyguanosine and deoxyadenosine with 1'-acetoxysafrole, 1'-hydroxysafrole-2',3'-oxide, and 1'-oxosafrole indicated that the four in vivo adducts studied were derived from an ester of 1'-hydroxysafrole. Three of the four in vivo adducts comigrated with adducts formed by reaction of 1'-acetoxysafrole with deoxyguanosine; the fourth adduct comigrated with the major product of the reaction of this ester with deoxyadenosine. Adduct formation in vivo at low levels by the other two electrophilic metabolites was not excluded. The three adducts obtained by reaction of 1'-acetoxysafrole with deoxyguanosine appeared to be substituted on the 2-amino group of the guanine residue on the basis of their partitions between aqueous buffer solutions and 1-butanol:ethyl ether as a function of pH and their retention of 3H from [8-3H]deoxyguanosine. The corresponding three adducts derived from the hepatic DNA of mice given 1'-[2',3'-3H]hydroxysafrole had pH partition patterns not significantly different from the three adducts formed in vitro. Adduct II was further characterized from its nuclear magnetic resonance spectrum as N2-(trans-isosafrol-3'-yl)deoxyguanosine. Adduct IV, derived from the reaction of 1'-acetoxysafrole with deoxyadenosine 5'-phosphate, was characterized in the same manner as N6-(trans-isosafrol-3'-yl)deoxyadenosine.
给成年雌性小鼠注射1'-[2'-3'-³H]羟基黄樟素后，肝脏中形成了与DNA、核糖体RNA和蛋白质结合的加合物，这些加合物在24小时内达到最高水平。在注射后1至3天之间，所有三种与大分子结合的加合物水平迅速下降，此时与DNA结合的加合物量基本稳定在最高水平的约15%。到20天时，蛋白质和核糖体RNA加合物的量非常低。通过高效液相色谱法比较从肝脏DNA中获得的脱氧核糖核苷加合物与脱氧鸟苷和脱氧腺苷与1'-乙酰氧基黄樟素、1'-羟基黄樟素-2',3'-氧化物和1'-氧代黄樟素反应形成的加合物，结果表明所研究的四种体内加合物均源自1'-羟基黄樟素的一种酯。四种体内加合物中的三种与1'-乙酰氧基黄樟素与脱氧鸟苷反应形成的加合物共迁移；第四种加合物与该酯与脱氧腺苷反应的主要产物共迁移。并不排除其他两种亲电代谢产物在体内形成低水平加合物的可能性。根据1'-乙酰氧基黄樟素与脱氧鸟苷反应得到的三种加合物在水缓冲溶液和1-丁醇：乙醚之间的分配随pH的变化情况以及它们从[8-³H]脱氧鸟苷中保留³H的情况，似乎是在鸟嘌呤残基的2-氨基上发生了取代。给予1'-[2',3'-³H]羟基黄樟素的小鼠肝脏DNA衍生的相应三种加合物的pH分配模式与体外形成的三种加合物没有显著差异。加合物II通过其核磁共振光谱进一步表征为N2-(反式异黄樟素-3'-基)脱氧鸟苷。源自1'-乙酰氧基黄樟素与脱氧腺苷5'-磷酸反应的加合物IV，以与N6-(反式异黄樟素-3'-基)脱氧腺苷相同的方式进行表征。
