477 Topical treatment of human skin and cultured keratinocytes with high-dose spironolactone reduces XPB expression and induces genotoxicity

Abstract

The mineralocorticoid and andogen receptor antagonist spironolactone (SP) is used to treat a variety of disparate disease states ranging from heart failure to acne. Though SP is usually taken as an oral medication, several recent studies have explored the administration of SP topically on the skin to avoid systemic effects in the body. Because SP induces the proteolytic degradation of the XPB (xeroderma pigmentosum group B) DNA translocase protein, which is involved in both DNA repair and transcription, SP may have genotoxic effects in the skin. Using skin explants, we show here that the topical application of a high concentration of either SP or its metabolite canrenone onto human skin induces the loss of the XPB protein and the phosphorylation of the histone variant H2AX, a common marker of genotoxicity. Though high concentrations of SP and canrenone both inhibit cell proliferation, induce H2AX phosphorylation, and stimulate apoptotic signaling in cultured keratinocytes in vitro, canrenone is much less potent at inducing the loss of XPB. Thus, high concentrations of SP and canrenone likely inhibit cell proliferation and induce genotoxicity via additional mechanisms besides XPB proteolytic degradation. Together, this work suggests that care may need to be taken when using high concentrations of SP directly on human skin.