STUDIES ON THE CONVERSION OF ANDROGENS TO ESTROGENS BY AROMATASE

芳香酶将雄激素转化为雌激素的研究

• 批准号: 3838486
• 负责人: K KORZEKWA
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838486
• 关键词: CHO cells; NAD(P)H oxidoreductase; aldehydes; androgens; aromatase; chemical reaction; cytochrome b; diol; enzyme activity; enzyme mechanism; enzyme model; estrogens; genetic regulation; human genetic material tag; model design /development; nicotinamide adenine dinucleotide; oxidation; oxygen; steroid hormone metabolism; transfection; vaccinia virus

Aromatase (CYP19A1) is the enzyme responsible for the conversion of androgens to estrogens. This enzyme has received considerable attention over the last 30 years, with much of the recent effort directed at the development of inhibitors to be used in the treatment of estrogen dependent breast cancer. This laboratory is focusing on the mechanistic and regulatory aspects of aromatase. It has been shown that three molecules of molecular oxygen and six reducing equivalents from NADPH are consumed during estrogen formation. The androgen is first oxidized to the C19-hydroxyandrogen and then oxidized to the C19 gemdiol, or its dehydrated form, the C19 aldehyde. The mechanism of the third oxidation is still undefined, even though considerable information regarding the reaction has been established over the years. Experimental and theoretical studies are underway which investigate the mechanism of the third oxidation of aromatase and other recently described P450 mediated deformylation reactions. In addition to other regulatory mechanisms, aromatase activity may also be regulated by the levels of cytochrome P450 reductase present. We have shown that the relative amounts of estrogen intermediates is dependent on the aromatase:reductase ratio. We are using Chinese hamster ovary cells (CHO) that stably express the human aromatase gene. The influence of cytochrome P450 reductase or cytochrome b5 on rates of aromatase catalysis are investigated by transfection of CHO cells with vaccinia virus containing the appropriate gene constructs. This system enables us to develop a working model of aromatase regulation by variation in ratios of ancillary proteins.

芳香化酶（CYP 19 A1）是一种负责将 从雄激素到雌激素 这种酶受到了相当大的关注 在过去的30年里，最近的大部分努力都是针对 用于治疗雌激素的抑制剂的开发 依赖性乳腺癌 这个实验室主要研究 和芳香酶的调节方面。 研究表明，三个氧分子和六个 在雌激素形成过程中，NADPH的还原当量被消耗。 雄激素首先被氧化成C19-羟基雄激素，然后 氧化成C19偕二醇或其脱水形式C19醛。 第三次氧化的机制仍然不确定，即使 关于该反应的大量信息已经建立在 这些年实验和理论研究正在进行中， 探讨芳香化酶第三氧化反应的机理， 最近描述了P450介导的脱髓鞘反应。 除了其他调节机制外，芳香酶活性也可能是 受细胞色素P450还原酶水平的调节。 我们有 表明雌激素中间体的相对量取决于 芳香酶：还原酶比率。 我们用的是中国仓鼠卵巢细胞 (CHO)稳定表达人类芳香化酶基因。 的影响 细胞色素P450还原酶或细胞色素b5对芳香酶催化速率的影响 通过用牛痘病毒转染CHO细胞来研究 含有合适的基因构建体。 该系统使我们能够 发展芳香化酶调节的工作模型， 辅助蛋白