A UNIQUE TESTOSTERONE METABOLITE--17BETA-HYDROXY 4,6-ANDROSTADIENE-3-ONE

一种独特的睾酮代谢物--17β-羟基4,6-雄甾二烯-3-酮

• 批准号: 3920011
• 负责人: K KORZEKWA
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 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/3920011
• 关键词: cytochrome P450; deuterium; enzyme mechanism; enzyme reconstitution; hydroxysteroids; isozymes; laboratory rat; steroid hormone analog; steroid hormone metabolism; testosterone; valproate

The purpose of this study is to probe the mechanism by which cytochrome P-450a converts testosterone to the metabolite I7beta- hydroxy-4,6-androstadiene-3-one (delta 6T). Previous work in this Laboratory, which showed that 6T formation paralleled 6-beta- hydroxylation, suggested that the 6 beta-hydroxylate catalyzed the reaction and led to the concept of a dual hydrogen atom abstraction mechanism. In addition, however, desaturation reaction is also catalyzed by cytochrome P-450a, which hydroxylates testosterone preferentially to 7 alpha-hydroxytestosterone. An analogous metabolite of valproate has also been reported. The objective of this work is to measure the deuterium isotope effects associated with the desaturation mechanism. Selectively deuterated testosterone derivatives were synthesized and subjected to metabolism by reconstituted systems of cytochrome p-450a. The isotope effects for delta 6T formation strongly support a stepwise mechanism in which the 6 alpha-hydrogen atom is initially abstracted, followed 7 alpha-hydrogen atom abstraction to generate the unsaturated metabolite and water.

本研究的目的是探讨 细胞色素P-450 a将睾酮转化为代谢物I7 β- 羟基-4，6-雄甾二烯-3-酮（δ 6 T）。 以前的工作在此 实验室，这表明，6 T形成的β 6-β- 羟基化，表明6 β-羟基化物催化了 反应，并导致了双氢原子抽象的概念 机制 然而，除此之外，去饱和反应也是 由细胞色素P-450 a催化， 优选7 α-羟基睾酮。 类似的 还报告了丙戊酸盐的代谢产物。 的目标 这项工作是为了测量氘同位素的影响， 去饱和机制。 选择性氘代 合成睾酮衍生物， 通过细胞色素P-450 a的重建系统进行代谢。 的 δ 6 T地层的同位素效应强烈支持一个逐步的 其中6 α-氢原子最初是 提取，随后提取7个α-氢原子， 不饱和代谢物和水。