SMOKING AND ESTROGEN METABOLISM RELATED TO CANCER RISK

一些流行病学研究表明，吸烟是 与显著的抗雌激素作用有关，这一事实是 与最近发现的子宫内膜癌发病率下降有关 绝经后女性吸烟者。其他与雌激素相关的生理因素 受影响的过程包括更年期提前，骨质疏松加重，以及 可能是因为女性吸烟者的乳腺癌发病率降低了。澄清： 吸烟影响雌激素分泌的潜在机制 病理生理学可能被证明在制定策略方面是有用的 预防子宫内膜癌和乳腺癌。 我们已经证明了雌二醇2-羟化的强大诱导性。 绝经前女性的放射性活体测量 每天至少抽15支烟，这可能是 雌激素在荷尔蒙靶组织的生物利用度降低。几个 众所周知，香烟烟雾的成分是引起癌症的强大诱因。 参与雌二醇代谢的肝微粒体P-450酶。 该实验室在使用辐射测量程序方面有丰富的经验 雌二醇的三个主要氧化转化的研究 C-2、C-16屈服和C-17在人类中的位置。C-2羟基化反应的研究 雌二醇在这些代谢步骤中是独一无二的，因为 在反应中形成的儿茶酚雌激素几乎没有外周 雌激素活性。因此，在这一代谢途径中的诱导将是 预期具有显著的抗雌激素作用，并可能解释 降低吸烟者患子宫内膜癌的风险。 我们将利用辐射测量方法进一步探讨吸烟的影响。 绝经后雌二醇2-羟化的研究 吸烟者与对照组；男性吸烟者与对照组；以及女性吸烟者 不同程度的烟草消费。我们将关联以下方面的变化 雌二醇2-羟化与血清尼古丁(或可持续)水平，以及 试图通过注射尼古丁来诱导雌激素代谢的变化 经皮下注射。我们将对女性吸烟者进行雌二醇2-羟化研究 已经戒烟了不同时期的人。最后，我们会 检查雌激素代谢的其他代谢途径，包括 不可逆的C-16产率羟基化步骤及芳构化反应 雄烯二酮到雌酮，为香烟诱导的进一步证据 抽烟。

Several epidemiological studies indicate that cigarette smoking is associated with a significant anti-estrogenic effect, and this fact is related to the recent finding of decreased endometrial cancer among postmenopausal female smokers. Other estrogen-related physiological processes affected include earlier menopause, increased osteoporosis, and possibly, decreased breast cancer among female smokers. Elucidation of the underlying mechanism whereby smoking affects estrogen disposition and pathophysiology may prove useful in developing strategies toward the prevention of endometrial and breast cancer. We have demonstrated a powerful induction of estradiol 2-hydroxylation measured in vivo with the radiometric procedure in premenopausal females smoking at least 15 cigarettes per day, possibly accounting for the decreased estrogen bioavailability at hormone target tissues. Several constituents of cigarette smoke are known to be powerful inducers of the hepatic microsomal P-450 enzymes participating in estradiol metabolism. This laboratory has extensive experience using radiometric procedures for studying the three principal oxidative transformations of estradiol at the C-2, C-16yield, and C-17 position in humans. The C-2 hydroxylation of estradiol is unique among these metabolic steps in that the catecholestrogens formed in the reaction are virtually devoid of peripheral estrogenic activity. Thus, induction in this metabolic pathway would be expected to have a significant anti-estrogenic effect, and may explain the reduced risk of endometrial cancer in smokers. We will use the radiometric method to further explore the effect of smoking on estradiol 2-hydroxylation in the following groups: postmenopausal smokers versus controls; male smokers versus controls; and, female smokers with different levels of tobacco consumption. We will correlate changes in estradiol 2-hydroxylation with serum nicotine (or continine) levels, and attempt to induce changes in estrogen metabolism by administering nicotine transdermally. We will follow esstradiol 2-hydroxylation in female smokers who have stopped smoking for various periods of time. Finally, we will examine other metabolic pathways of estrogen metabolism, including the irreversible C-16yield hydroxylation step, and the aromatization of androstenedione to estrone, for further evidence of induction by cigarette smoking.