Department of Biological Sciences, University of Texas at El Paso, El Paso, TX, USA.
Gen Comp Endocrinol. 2010 May 15;167(1):51-9. doi: 10.1016/j.ygcen.2010.02.019. Epub 2010 Feb 21.
The multidrug resistance-associated protein 1 (MRP1/ABCC1) is a member of the ABC active transporter family that can transport several steroid hormone conjugates, including 17beta-estradiol glucuronide, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate. The present study investigated the role that MRP1 plays in maintaining proper hormone levels in the serum and testes. Serum and testicular steroid hormone levels were examined in both wild-type mice and Mrp1 null mice. Serum testosterone levels were reduced 5-fold in mice lacking Mrp1, while testicular androstenedione, testosterone, estradiol, and dehydroepiandrosterone (DHEA) were significantly reduced by 1.7- to 4.5-fold in Mrp1 knockout mice. Investigating the mechanisms responsible for the reduction in steroid hormones in Mrp1-/- mice revealed no differences in the expression or activity of enzymes that inactivate steroids, the sulfotransferases or glucuronosyltransferases. However, steroid biosynthetic enzyme levels in the testes were altered. Cyp17 protein levels were increased by 1.6-fold, while Cyp17 activity using progesterone as a substrate was also increased by 1.4- to 2.0-fold in mice lacking Mrp1. Additionally, the ratio of 17beta-hydroxysteroid dehydrogenase to 3beta-hydroxysteroid dehydrogenase, and steroidogenic factor 1 to 3beta-hydroxysteroid dehydrogenase were significantly increased in the testes of Mrp1-/- mice. These results indicate that Mrp1-/- mice have lowered steroid hormones levels, and suggests that upregulation of steroid biosynthetic enzymes may be an attempt to maintain proper steroid hormone homeostasis.
多药耐药相关蛋白 1（MRP1/ABCC1）是 ABC 主动转运蛋白家族的一员，可转运多种甾体激素缀合物，包括 17β-雌二醇葡萄糖醛酸、脱氢表雄酮硫酸酯（DHEAS）和雌酮 3-硫酸盐。本研究探讨了 MRP1 在维持血清和睾丸中适当激素水平中的作用。在野生型小鼠和 Mrp1 缺失小鼠中检查了血清和睾丸甾体激素水平。缺乏 Mrp1 的小鼠血清睾酮水平降低了 5 倍，而 Mrp1 敲除小鼠的睾丸雄烯二酮、睾酮、雌二醇和脱氢表雄酮（DHEA）分别降低了 1.7 至 4.5 倍。研究导致 Mrp1-/-小鼠中甾体激素减少的机制表明，失活甾体的酶、硫酸转移酶或葡萄糖醛酸转移酶的表达或活性没有差异。然而，睾丸中甾体生物合成酶的水平发生了改变。Cyp17 蛋白水平增加了 1.6 倍，而缺乏 Mrp1 的小鼠中使用孕酮作为底物的 Cyp17 活性也增加了 1.4 至 2.0 倍。此外，Mrp1-/-小鼠睾丸中 17β-羟甾脱氢酶与 3β-羟甾脱氢酶的比值以及类固醇生成因子 1 与 3β-羟甾脱氢酶的比值显著增加。这些结果表明，Mrp1-/-小鼠的甾体激素水平降低，表明甾体生物合成酶的上调可能是维持适当甾体激素动态平衡的一种尝试。
