Topical Treatment of Human Skin and Cultured Keratinocytes with High-Dose Spironolactone Reduces XPB Expression and Induces Toxicity

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.