Moon Changsuk, Zhang Weiqiang, Sundaram Nambirajan, Yarlagadda Sunitha, Reddy Vadde Sudhakar, Arora Kavisha, Helmrath Michael A, Naren Anjaparavanda P
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Pharmacol Res. 2015 Dec;102:107-112. doi: 10.1016/j.phrs.2015.08.024. Epub 2015 Sep 30.
Many medications induce diarrhea as a side effect, which can be a major obstacle to therapeutic efficacy and also a life-threatening condition. Secretory diarrhea can be caused by excessive fluid secretion in the intestine under pathological conditions. The cAMP/cGMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) is the primary chloride channel at the apical membrane of intestinal epithelial cells and plays a major role in intestinal fluid secretion and homeostasis. CFTR forms macromolecular complexes at discreet microdomains at the plasma membrane, and its chloride channel function is regulated spatiotemporally through protein-protein interactions and cAMP/cGMP-mediated signaling. Drugs that perturb CFTR-containing macromolecular complexes in the intestinal epithelium and upregulate intracellular cAMP and/or cGMP levels can hyperactivate the CFTR channel, causing excessive fluid secretion and secretory diarrhea. Inhibition of CFTR chloride-channel activity may represent a novel approach to the management of drug-induced secretory diarrhea.
许多药物会引起腹泻这一副作用，这可能成为治疗效果的主要障碍，也是一种危及生命的状况。分泌性腹泻可由病理状态下肠道中过多的液体分泌引起。环磷酸腺苷/环磷酸鸟苷调节的囊性纤维化跨膜传导调节因子（CFTR）是肠道上皮细胞顶端膜上的主要氯离子通道，在肠道液体分泌和体内平衡中起主要作用。CFTR在质膜上离散的微结构域形成大分子复合物，其氯离子通道功能通过蛋白质-蛋白质相互作用和环磷酸腺苷/环磷酸鸟苷介导的信号传导在时空上受到调节。扰乱肠道上皮中含CFTR的大分子复合物并上调细胞内环磷酸腺苷和/或环磷酸鸟苷水平的药物可过度激活CFTR通道，导致过多的液体分泌和分泌性腹泻。抑制CFTR氯离子通道活性可能代表一种治疗药物性分泌性腹泻的新方法。
