Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: Potential biomarkers for estrogen-initiated cancer
Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: Potential biomarkers for estrogen-initiated cancer
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DOI：
10.1093/carcin/22.3.489
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发表时间：
2001-03-01
期刊：
影响因子：
4.7
通讯作者：
Cavalieri, EL
中科院分区：
文献类型：
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作者：
Devanesan, P;Todorovic, R;Cavalieri, EL
邻苯二酚雌激素-3，4-醌与DNA反应形成脱嘌呤加合物被认为是雌激素的肿瘤起始事件[E.L. Cavalieri等人（1997）Proc，Natl Acad，Sci，USA，94，10937-10942]，在雌激素失衡下，儿茶酚雌激素氧化成醌可能与它们通过保护酶的解毒作用竞争，所形成的醌可以通过与谷胱甘肽（CSH）反应而解毒或可以共价结合到DNA。我们开发了一种方法来鉴定和定量通过腹膜内注射用4-羟基雌激素（4-OHE 2）处理的雄性叙利亚仓鼠的肾脏中4-羟基雌激素（4-OHE）的GSH、半胱氨酸（Cys）和N-乙酰Cys缀合物。在处理后1小时观察到最高水平的缀合物，并且在24小时后几乎检测不到缀合物，剂量反应研究表明，用0.5 μ mol 4-OHE 2/100 g体重处理后形成缀合物，并且形成增加至12 μ mol/100 g体重的处理水平，GSH，4-OHE的Cys和N-乙酰Cys缀合物在皮摩尔范围内通过高效液相色谱法（HPLC）和多通道电化学检测进行鉴定，并通过HPLC/HPLC串联质谱法，在提取前用β-葡糖醛酸酶/硫酸酯酶在37 ℃处理组织匀浆6小时，导致Cys缀合物从皮摩尔水平增加到纳摩尔水平的12- 20倍，通过仅在37 ℃温育组织6小时观察到类似的增强，通过质谱法获得4-OHE-1-N7 Gua脱嘌呤加合物的证据。我们得出的结论是，4-OHE和4-OHE-N7 Gua加合物的GSH和Cys缀合物可用作生物标志物来检测雌激素失衡和对肿瘤发生的潜在易感性。
Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L. Cavalieri et al. (1997) Proc, Natl Acad, Sci, USA, 94, 10937-10942], Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes, The quinones formed can be detoxified by reaction with glutathione (CSH) or can covalently bind to DNA, To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-hydroxyestradiol (4-OHE2) by intraperitoneal injection, The highest level of conjugates was observed 1 fi after treatment, and almost none was detected after 24 h, Dose-response studies indicated conjugate formation after treatment with 0.5 mu mol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 mu mol/100 g body weight, GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by highperformance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry, Treatment of tissue homogenates with beta -glucuronidase/sulfatase at 37 degreesC for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels, Similar enhancement was observed by just incubating the tissue at 37 degreesC for 6 h, Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.