Tsuchiya Yuki, Nakajima Miki, Yokoi Tsuyoshi
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Cancer Lett. 2005 Sep 28;227(2):115-24. doi: 10.1016/j.canlet.2004.10.007. Epub 2004 Nov 19.
Estrogens are eliminated from the body by metabolic conversion to estrogenically inactive metabolites that are excreted in the urine and/or feces. The first step in the metabolism of estrogens is the hydroxylation catalyzed by cytochrome P450 (CYP) enzymes. Since most CYP isoforms are abundantly expressed in liver, the metabolism of estrogens mainly occurs in the liver. A major metabolite of estradiol, 2-hydroxyestradiol, is mainly catalyzed by CYP1A2 and CYP3A4 in liver, and by CYP1A1 in extrahepatic tissues. However, CYP1B1 which is highly expressed in estrogen target tissues including mammary, ovary, and uterus, specifically catalyzes the 4-hydroxylation of estradiol. Since 4-hydroxyestradiol generates free radicals from the reductive-oxidative cycling with the corresponding semiquinone and quinone forms, which cause cellular damage, the specific and local formation of 4-hydroxyestradiol is important for breast and endometrial carcinogenesis. Changes in the expression level of estrogen-metabolizing CYP isoforms not only alter the intensity of the action of estrogen but may also alter the profile of its physiological effect in liver and target tissues. Generally, many CYP isoforms are induced by the substrates themselves, resulting in enhanced metabolism and elimination from the body. Of particular interest is a novel finding that human CYP1B1 is regulated by estradiol via the estrogen receptor. This fact suggests that the regulation of CYP enzymes involved in estrogen metabolism by estrogen itself would be physiologically significant for the homeostasis of estrogens at local organs. In this mini-review, we discuss the CYP-mediated metabolism of estrogens and the regulation of the estrogen-metabolizing CYP enzymes in relation to the risk of cancer.
雌激素通过代谢转化为雌激素无活性的代谢产物而从体内消除，这些代谢产物经尿液和/或粪便排出。雌激素代谢的第一步是由细胞色素P450（CYP）酶催化的羟基化反应。由于大多数CYP同工型在肝脏中大量表达，因此雌激素的代谢主要发生在肝脏。雌二醇的主要代谢产物2-羟基雌二醇主要由肝脏中的CYP1A2和CYP3A4以及肝外组织中的CYP1A1催化。然而，在包括乳腺、卵巢和子宫在内的雌激素靶组织中高表达的CYP1B1特异性催化雌二醇的4-羟基化反应。由于4-羟基雌二醇通过与相应的半醌和醌形式的氧化还原循环产生自由基，从而导致细胞损伤，因此4-羟基雌二醇的特异性和局部形成对于乳腺癌和子宫内膜癌的发生很重要。雌激素代谢CYP同工型表达水平的变化不仅会改变雌激素的作用强度，还可能改变其在肝脏和靶组织中的生理效应谱。一般来说，许多CYP同工型由底物本身诱导，导致代谢增强并从体内消除。特别值得关注的是一项新发现，即人类CYP1B1受雌二醇通过雌激素受体的调节。这一事实表明，雌激素本身对参与雌激素代谢的CYP酶的调节对于局部器官雌激素的稳态在生理上具有重要意义。在本综述中，我们讨论了CYP介导的雌激素代谢以及与癌症风险相关的雌激素代谢CYP酶的调节。
