Identification of estrogen-modified nucleosides from calf thymus DNA reacted with 6-hydroxyestrogen 6-sulfates
Identification of estrogen-modified nucleosides from calf thymus DNA reacted with 6-hydroxyestrogen 6-sulfates
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DOI：
10.1021/tx9800957
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发表时间：
1998-11-01
影响因子：
4.1
通讯作者：
Yoshizawa, I
中科院分区：
文献类型：
--
作者：
Itoh, S;Hirai, T;Yoshizawa, I
合成了两个雌激素硫酸盐，即3-甲氧基-1，3，5(10)-三烯-6α-硫代吡啶(3MeE-6α-S)及其GP异构体(3MeE-6β-S)，作为雌激素致癌的模型化合物，它们与小牛胸腺DNA反应生成类固醇修饰的DNA加合物。用核酸酶P1、磷酸二酯酶I和碱性磷酸酶消化DNA，得到脱氧核糖核苷组分，其中N-2-[3-甲氧基-1，3，5(10)-三烯-6α-基]脱氧鸟苷，N-2-[3-甲氧基-1，3，5(10)-三烯-6β-基]脱氧鸟苷，N-6-[3-甲氧基-1，3，5(10)-三烯-6α-基]脱氧腺苷5(10)三烯-6α-脱氧腺苷(被鉴定为碱基加合物)通过与反应DG制备的正品进行比较而得到鉴定；和两种硫酸盐的DA。在DNA加合物的消化产物中没有检测到类固醇-DC加合物，尽管DC与硫酸盐反应生成了N-4-[3-甲氧基-1，3，5(10)-三烯-G-β-基]脱氧胞苷，但这些结果表明B-硫酸盐雌激素具有通过DNA中鸟嘌呤或腺嘌呤残基的氨基修饰DNA的能力。目前的研究表明，雌激素分子Cs位的一系列代谢(羟化和硫酸盐化)会对DNA造成损伤。
Two estrogen sulfates, pyridinium 3-methoxyestra-1,3,5(10)-trien-6 alpha-yl sulfate (3MeE-6 alpha-S) and its GP-isomer (3MeE-6 beta-S), synthesized as model compounds to demonstrate the carcinogenesis of estrogen, were found to react with calf thymus DNA to produce steroid-modified DNA adducts. Digestion of the DNA by nuclease P1 and phosphodiesterase I followed by alkaline phosphatase gave a deoxyribonucleoside fraction, of which N-2-[3-methoxyestra-1,3,5( 10)-trien-6 alpha-yl]deoxyguanosine, N-2-[3-methoxyestra-1,3,5( 10)-trien-6 beta-yl]deoxyguanosine, N-6-[3-methoxyestra-1,3,5(10)-trien-6 alpha-yl]deoxyadenosine, and N-6-[3-methoxyestra-1,3,5(10)trien-6 alpha-yl]deoxyadenosine (identified as a base adduct) were identified using HPLC by comparing them with authentic specimens prepared by reacting dG; and dA with both sulfates. No steroid-dC adduct was detected in the digestion products of the DNA adduct, although dC reacted with the sulfates to form N-4-[3-methoxyestra-1,3,5(10)-trien-G beta-yl] deoxycytidine, These results mean that estrogen B-sulfate has an ability to modify DNA via the amino group of a guanine or adenine residue in DNA. The present studies imply that a sequential metabolism (hydroxylation and sulfation) at the Cs-position of the estrogen molecule causes damage to DNA.