Ma Jixiang, Graves Joan, Bradbury J Alyce, Zhao Yun, Swope Deborah L, King Lorraine, Qu Wei, Clark James, Myers Page, Walker Vickie, Lindzey Jonathan, Korach Kenneth S, Zeldin Darryl C
Division of Intramural Research, National Institutes of Health/NIEHS, Research Triangle Park, NC 27709, USA.
Mol Pharmacol. 2004 Mar;65(3):730-43. doi: 10.1124/mol.65.3.730.
Mouse CYP2J5 is abundant in kidney and active in the metabolism of arachidonic acid to epoxyeicosatrienoic acids. Western blots of microsomes prepared from mouse kidneys demonstrate that after puberty, CYP2J5 protein is present at higher levels in male mice than in female mice. Northern analysis reveals that CYP2J5 transcripts are more abundant in adult male versus female kidneys, indicating that gender differences in renal CYP2J5 expression are regulated at a pretranslational level. Castration of male mice results in decreased renal CYP2J5 expression, and treatment of castrated male mice or female mice with 5alpha-dihydrotestosterone increases expression to levels that approximate those in intact male mice. In contrast, treatment of ovariectomized female mice or castrated male mice with 17beta-estradiol causes a further reduction in CYP2J5 expression. Growth hormone-deficient (lit/lit) mice respond similarly to castration and 5alpha-dihydrotestosterone treatment, indicating that the androgen effects are not mediated by alterations in the growth hormone secretory pattern. Mice that lack a functional androgen receptor (Tfm hemizygous) have reduced levels of renal CYP2J5 and do not respond to 5alpha-dihydrotestosterone treatment. Similarly, wild-type male mice treated with flutamide, an androgen antagonist, exhibit reduced renal CYP2J5 levels. Female estrogen receptor-alpha knockout (alphaERKO) mice, which are known to have elevated circulating testosterone levels, have significantly increased renal CYP2J5 expression compared with wild-type female mice, and these differences are abrogated by ovariectomy or treatment with flutamide. Based on these data, we conclude that the renal expression of CYP2J5 is up-regulated by androgen and down-regulated by estrogen.
小鼠CYP2J5在肾脏中含量丰富，并且在将花生四烯酸代谢为环氧二十碳三烯酸的过程中具有活性。对从小鼠肾脏制备的微粒体进行蛋白质免疫印迹分析表明，青春期后，雄性小鼠肾脏中CYP2J5蛋白的水平高于雌性小鼠。Northern印迹分析显示，成年雄性小鼠肾脏中CYP2J5转录本比雌性小鼠更为丰富，这表明肾脏中CYP2J5表达的性别差异在翻译前水平受到调控。切除雄性小鼠的睾丸会导致肾脏中CYP2J5表达降低，而用5α-二氢睾酮处理去势雄性小鼠或雌性小鼠会使表达增加至接近完整雄性小鼠的水平。相反，用17β-雌二醇处理去卵巢雌性小鼠或去势雄性小鼠会导致CYP2J5表达进一步降低。生长激素缺乏（lit/lit）小鼠对去势和5α-二氢睾酮处理的反应相似，这表明雄激素的作用不是由生长激素分泌模式的改变介导的。缺乏功能性雄激素受体（Tfm半合子）的小鼠肾脏中CYP2J5水平降低，并且对5α-二氢睾酮处理无反应。同样，用雄激素拮抗剂氟他胺处理的野生型雄性小鼠肾脏中CYP2J5水平降低。已知循环睾酮水平升高的雌性雌激素受体α基因敲除（αERKO）小鼠与野生型雌性小鼠相比，肾脏中CYP2J5表达显著增加，而去卵巢或用氟他胺处理可消除这些差异。基于这些数据，我们得出结论，CYP2J5的肾脏表达受雄激素上调，受雌激素下调。
