Progesterone oxidation by cytochrome P450 2D isoforms in the brain
Progesterone oxidation by cytochrome P450 2D isoforms in the brain
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DOI：
10.1210/en.142.9.3901
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发表时间：
2001-09-01
期刊：
影响因子：
4.8
通讯作者：
Funae, Y
中科院分区：
文献类型：
--
作者：
Hiroi, T;Kishimoto, W;Funae, Y
细胞色素P450 2D异构体在脑中的存在已被证明，但其生理功能仍有待阐明。在这项研究中，我们证明了重组大鼠细胞色素P450 2D 1和2D 4以及人细胞色素P450 2D 6分别具有孕酮6 β-和16 α-羟基化活性; 2 β-和21-羟基化活性;以及2 β-、6 β-、16 α-和21-羟基化活性。细胞色素P450 2D 4对这些活性的Km值最低，最大速率值最高。在大鼠脑微粒体中也检测到孕酮2 β-和21-羟基化活性，并且这些活性被抗细胞色素P450 2D抗体完全抑制。还证明了大鼠脑组织中存在内源性2 β-和21-羟基胆甾酮。在大鼠脑中检测到细胞色素P450 2D 4、CYP 11 A和3 β-羟基类固醇脱氢酶的mRNA，表明孕酮在大鼠脑中由胆固醇经CYP 11 A和3 β-羟基类固醇脱氢酶生成，然后经细胞色素P450 2D 4羟基化为羟基甾酮。总的来说，我们的研究结果支持的想法，细胞色素P450 2D可能参与调节（代谢和/或合成）的内源性神经活性类固醇，如孕酮及其衍生物，在脑组织中。
The existence of cytochrome P450 2D isoforms in the brain has been demonstrated, although their physiological functions remain to be elucidated. In this study we demonstrated that recombinant rat cytochrome P450 2D1 and 2D4 and human cytochrome P450 2D6 possess progesterone 6 beta- and 16 alpha -hydroxylation activities; 2 beta- and 21-hydroxylation activities; and 2 beta-,6 beta-,16 alpha- and 21-hydroxylation activities, respectively. Cytochrome P450 2D4 had the lowest K-m value and the highest maximum velocity value toward these activities. Progesterone 2 beta- and 21-hydroxylation activities were also detected in rat brain microsomes, and these activities were completely inhibited by anticytochrome P450 2D antibodies. The presence of endogenous 2 beta- and 21-hydroxyprogesterones in rat brain tissues was also demonstrated. The mRNAs of cytochrome P450 2D4, CYP11A, and 3 beta -hydroxysteroid dehydrogenase were detected in the rat brain, suggesting that progesterone was generated from cholesterol by CYP11A and 3 beta -hydroxysteroid dehydrogenase and then underwent hydroxylation to hydroxyprogesterones by cytochrome P450 2D4 in rat brain. Collectively, our findings support the idea that cytochrome P450 2D may be involved in the regulation (metabolism and/or synthesis) of endogenous neuroactive steroids, such as progesterone and its derivatives, in brain tissues.