Mechanisms of the actions of aromatase inhibitors 4-hydroxyandrostenedione, fadrozole, and aminoglutethimide on aromatase in JEG-3 cell culture
Mechanisms of the actions of aromatase inhibitors 4-hydroxyandrostenedione, fadrozole, and aminoglutethimide on aromatase in JEG-3 cell culture
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DOI：
10.1016/s0960-0760(97)00072-1
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发表时间：
1997-11-01
影响因子：
4.1
通讯作者：
Brodie, AMH
中科院分区：
文献类型：
--
作者：
Yue, W;Brodie, AMH
已经发现用芳香酶抑制剂选择性抑制雌激素产生是治疗乳腺癌的有效策略。大多数研究集中在抑制剂筛选和体外动力学分析的芳香化酶抑制胎盘微粒体。为了确定不同抑制剂对整个细胞中芳香化酶的影响，我们利用培养的人绒毛膜癌细胞系JEG-3来比较和研究三类芳香化酶抑制剂，4-羟基雄烯二酮，法倔唑（CGS 16949 A）和氨基谷氨酰胺。法倔唑是最有效的竞争性抑制剂，氨鲁米特是最有效的三者。然而，芳香化酶活性的刺激被发现发生时，JEG-3细胞与氨鲁米特预孵育。与此相反，4-OHA和法倔唑引起持续抑制芳香化酶活性在JEG-3细胞和胎盘微粒体，这是不逆转，即使在去除抑制剂。4-OHA与芳香化酶的活性位点不可逆地结合，导致芳香化酶失活，其失活遵循伪一级动力学。然而，4-OHA似乎在JEG-3细胞中代谢迅速。法倔唑诱导的芳香化酶的持续抑制通过不同的机制发生。尽管法倔唑在不同于类固醇结合位点的位点与芳香酶紧密结合，但法倔唑对芳香酶活性的抑制不涉及反应过程。没有抑制剂刺激芳香化酶mRNA的合成在JEG-3细胞在8小时的治疗。AG对芳香化酶活性的刺激似乎是由于芳香化酶蛋白的稳定。根据这些结果，预计4-OHA和法倔唑在乳腺癌患者的治疗中比AG更有益。AG增加芳香化酶活性可能会抵消其治疗效果，并可能是乳腺癌患者从这种治疗中复发的部分原因。(C)1997 Elsevier Science Ltd.保留所有权利。
Selective inhibition of estrogen production with aromatase inhibitors has been found to be an effective strategy for breast cancer treatment. Most studies have focused on inhibitor screening and in vitro kinetic analysis of aromatase inhibition using placental microsomes. In order to determine the effects of different inhibitors on aromatase in the whole cell, we have utilized the human choriocarcinoma cell line, JEG-3 in culture to compare and study three classes of aromatase inhibitors, 4-hydroxyandrostenedione, fadrozole (CGS 16949A), and amino glutethimide. Fadrozole is the most potent competitive inhibitor and aminoglutethimide is the least potent among the three. However, stimulation of aromatase activity was found to occur when JEG-3 cells were preincubated with aminoglutethimide. In contrast, 4-OHA and fadrozole caused sustained inhibition of aromatase activity in both JEG-3 cells and placental microsomes, which was not reversed even after the removal of the inhibitors. 4-OHA bound irreversibly to the active site of aromatase and caused inactivation of the enzyme which followed pseudo-first order kinetics. However, 4-OHA appears to be metabolized rapidly in JEG-3 cells. Sustained inhibition of aromatase induced by fadrozole occurs by a different mechanism. Although fadrozole bound tightly to aromatase at a site distinct from the steroid binding site, the inhibition of aromatase activity by fadrozole does not involve a reactive process. None of the inhibitors stimulated aromatase mRNA synthesis in JEG-3 cells during 8 h treatment. The stimulation of aromatase activity by AG appeared to be due to stabilization of aromatase protein. According to these results, 4-OHA and fadrozole would be expected to be more beneficial in the treatment of breast cancer patients than AG. The increase in aromatase activity by AG may counteract its therapeutic effect and might be partially responsible for relapse of breast cancer patients from this treatment. (C) 1997 Elsevier Science Ltd. All rights reserved.