Carpenter M Alexandra, Kemp Michael G
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
JID Innov. 2021 May 6;1(3):100023. doi: 10.1016/j.xjidi.2021.100023. eCollection 2021 Sep.
Spironolactone (SP) is used to treat a variety of disparate disease states ranging from heart failure to acne through antagonism of the mineralocorticoid and androgen receptors. Although normally taken as an oral medication, recent studies have explored the topical application of SP onto the skin. However, because SP induces the proteolytic degradation of the XPB protein, which plays critical roles in DNA repair and transcription, there may be safety concerns with the use of topical SP. In this study, we show that the topical application of a high concentration of either SP or its metabolite canrenone onto human skin ex vivo lowers XPB protein levels and induces toxic responses in the epidermis. Interestingly, although SP and canrenone both inhibit cell proliferation, induce replication stress responses, and stimulate apoptotic signaling at high concentrations in cultured keratinocytes in vitro, these effects were not correlated with XPB protein loss. Thus, high concentrations of SP and canrenone likely inhibit cell proliferation and induce toxicity through additional mechanisms to XPB proteolytic degradation. This work suggests that care may need to be taken when using high concentrations of SP directly on human skin.
螺内酯（SP）通过拮抗盐皮质激素和雄激素受体，用于治疗从心力衰竭到痤疮等多种不同的疾病状态。尽管通常作为口服药物服用，但最近的研究探索了SP在皮肤上的局部应用。然而，由于SP会诱导XPB蛋白的蛋白水解降解，而XPB蛋白在DNA修复和转录中起关键作用，因此局部使用SP可能存在安全问题。在本研究中，我们表明，在体外将高浓度的SP或其代谢产物坎利酮局部应用于人体皮肤会降低XPB蛋白水平，并在表皮中诱导毒性反应。有趣的是，尽管SP和坎利酮在体外培养的角质形成细胞中高浓度时均能抑制细胞增殖、诱导复制应激反应并刺激凋亡信号传导，但这些作用与XPB蛋白丢失无关。因此，高浓度的SP和坎利酮可能通过XPB蛋白水解降解以外的其他机制抑制细胞增殖并诱导毒性。这项工作表明，直接在人体皮肤上使用高浓度的SP时可能需要谨慎。
