Rayyan Esa, Polito Sarah, Leung Lana, Bhakta Ashesh, Kang Jonathan, Willey Justin, Mansour Wasim, Drumm Mitchell L, Al-Nakkash Layla
Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA.
Pediatric Pulmonology Division, Case Western Reserve University, Cleveland, OH, USA.
Clin Exp Gastroenterol. 2015 Jan 30;8:77-87. doi: 10.2147/CEG.S72111. eCollection 2015.
Cystic fibrosis (CF) results from the loss or reduction in function of the CFTR (cystic fibrosis transmembrane conductance regulatory protein) chloride channel. The third most common CFTR mutation seen clinically is R117H. Genistein, a naturally occurring phytoestrogen, is known to stimulate CFTR function in vitro. We aimed to determine whether route of administration of genistein could mediate differential effects in R117H male and female CF mice. Mice were fed (4 weeks) or injected subcutaneously (1 week) with the following: genistein 600 mg/kg diet (600Gd); genistein-free diet (0Gd); genistein injection 600 mg/kg body weight (600Gi); dimethyl sulfoxide control (0Gi). In male R117H mice fed 600Gd, basal short circuit current (Isc) was unchanged. In 600Gd-fed female mice, there was a subgroup that demonstrated a significant increase in basal Isc (53.14±7.92 μA/cm(2), n=6, P<0.05) and a subgroup of nonresponders (12.05±6.59 μA/cm(2), n=4), compared to 0Gd controls (29.3±6.5 μA/cm(2), n=7). In R117H mice injected with 600Gi, basal Isc was unchanged in both male and female mice compared to 0Gi controls. Isc was measured in response to the following: the adenylate cyclase activator forskolin (10 μM, bilateral), bumetanide (100 μM, basolateral) to indicate the Cl(-) secretory component, and acetazolamide (100 μM, bilateral) to indicate the HCO3 (-) secretory component; however, there was no effect of genistein (diet or injection) on any of these parameters. Jejunal morphology (ie, villi length, number of goblet cells per villus, crypt depth, and number of goblet cells per crypt) in R117H mice suggested no genistein-mediated difference among the groups. Serum levels of genistein were significantly elevated, compared to respective controls, by either 600Gd (equally elevated in males and females) or 600Gi (elevated more in females versus males). These data suggest a sex-dependent increase in basal Isc of R117H mice and that the increase is also specific for route of administration.
囊性纤维化（CF）是由囊性纤维化跨膜传导调节蛋白（CFTR）氯离子通道功能丧失或降低所致。临床上第三常见的CFTR突变是R117H。染料木黄酮是一种天然存在的植物雌激素，已知其在体外可刺激CFTR功能。我们旨在确定染料木黄酮的给药途径是否能在R117H雄性和雌性CF小鼠中产生不同的效应。给小鼠喂食（4周）或皮下注射（1周）以下物质：含600 mg/kg染料木黄酮的饮食（600Gd）；不含染料木黄酮的饮食（0Gd）；600 mg/kg体重的染料木黄酮注射剂（600Gi）；二甲亚砜对照（0Gi）。在喂食600Gd的雄性R117H小鼠中，基础短路电流（Isc）未发生变化。在喂食600Gd的雌性小鼠中，与0Gd对照组（29.3±6.5 μA/cm²，n = 7）相比，有一个亚组的基础Isc显著增加（53.14±7.92 μA/cm²，n = 6，P<0.05），还有一个无反应亚组（12.05±6.59 μA/cm²，n = 4）。在注射600Gi的R117H小鼠中，与0Gi对照组相比，雄性和雌性小鼠的基础Isc均未发生变化。测量Isc以响应以下刺激：腺苷酸环化酶激活剂福斯可林（10 μM，双侧）、布美他尼（100 μM，基底外侧）以指示Cl⁻分泌成分，以及乙酰唑胺（100 μM，双侧）以指示HCO₃⁻分泌成分；然而，染料木黄酮（饮食或注射）对这些参数均无影响。R117H小鼠的空肠形态（即绒毛长度、每个绒毛杯状细胞数量、隐窝深度以及每个隐窝杯状细胞数量）表明各实验组之间不存在染料木黄酮介导的差异。与各自的对照组相比，600Gd（雄性和雌性中同等升高）或600Gi（雌性升高幅度大于雄性）均使血清染料木黄酮水平显著升高。这些数据表明R117H小鼠的基础Isc存在性别依赖性增加，并且这种增加也因给药途径而异。
