REGULATION OF CYTOCHROME P450'S IN ADRENAL

肾上腺细胞色素 P450 的调节

• 批准号: 3239547
• 负责人: VIRGINIA H BLACK
• 金额: $ 16.19万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3239547
• 关键词: adrenal glands; adrenocorticotropic hormone; androgens; animal age group; antibody; biotransformation; cytochrome P450; gender difference; guinea pigs; hydroxylation; liver metabolism; messenger RNA; methylcholanthrene; microsomes; molecular cloning; pituitary gonadal axis; steroid metabolism; western blottings

In the guinea pig adrenal, the zona reticularis occupies over 50% of the cortical mass in adult males. The ability of the adrenal to metabolize foreign compounds is localized to the microsomes obtained from this zone. This capacity for xenobiotic metabolism increases with age, is greater in males than in females, and is suppressed by ACTH treatment, and is male- specific. This 52K protein does not react with antibodies against known adrenal microsomal steroid hydroxylases (P45021 and P45017alpha), but does react with antibody against methylcholanthrene-induced P450s in rat liver (P450c,d). Several hepatic cytochrome P450s have been shown to hydroxylate androgens at specific sites on the sterol ring, in addition to their capacity for xenobiotic metabolism. Some of these are sex-dependent. This is the first direct indication of a sex-dependent P450 in the adrenal. Whether it is specific for metabolism of foreign compounds or has functions in as yet undescribed male-specific steroid hydroxylation needs to be determined. Its relationship to P450c,d is of particular interest since neither of these proteins is known to be sex-dependent. The inner zone localization of this male-specific cytochrome P450 places it in an ideal position to modify steroids secreted by the outer zone. Its suppression by ACTH could provide an intraadrenal regulator of total steroid output. Analysis of its regulation by gonadal and pituitary hormones needs to be investigated. It is the purpose of this proposal: (1) To define the function of this male-specific P450 in xenobiotic vs steroid metabolism. (2) To investigate regulation of this P450 by gonadal and pituitary hormones at the protein and mRNA levels. (3) To investigate the relationship of this P450 to other members of this gene superfamily by cloning and sequence analysis.

在豚鼠肾上腺中，网状层占肾上腺皮质的50%以上。 成年男性的皮质块。 肾上腺代谢的能力 外来化合物定位于从该区域获得的微粒体。 这种异生物质代谢的能力随着年龄的增长而增加， 而在女性中，男性比女性更容易被ACTH抑制， 特定. 这种52K蛋白质不与已知的抗体反应。 肾上腺微粒体类固醇羟化酶（P45021和P45017 α），但 与抗甲基胆蒽诱导的大鼠肝P450抗体反应 （P450 c，d）。 几种肝细胞色素P450已被证明可以羟化雄激素 在甾醇环上的特定位点，除了它们的能力， 异生物代谢 其中一些是依赖于性别的。 这是第一 直接表明肾上腺中存在性别依赖性P450。 无论是 特异于外源化合物的代谢，或在 需要确定未描述的雄性特异性类固醇羟基化。 它与P450c，d的关系特别令人感兴趣，因为 已知这些蛋白质是性别依赖性的。 这种雄性特异性细胞色素P450的内区定位将其置于 在一个理想的位置来修改外区分泌的类固醇。 其 ACTH的抑制可以提供一种肾上腺内调节剂， 类固醇输出。 性腺和垂体对其调节作用的分析 激素需要研究。 本提案的目的是： (1)为了确定这种雄性特异性P450在外源性与非外源性之间的功能， 类固醇代谢 (2)研究性腺和垂体对P450的调节 在蛋白质和mRNA水平的激素。 (3)为了研究P450与其他成员的关系， 基因超家族的研究。