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Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin

Michael G Kemp1, Smita Krishnamurthy2, Michael N Kent3

  • 1Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.

The Journal of Investigative Dermatology
|September 19, 2018
PubMed

Insights

Spironolactone (SP) hinders DNA repair by degrading the XPB protein, increasing susceptibility to UVB damage and potentially raising skin cancer risk. This highlights SP

Area of Science:

  • Dermatology
  • Molecular Biology
  • Genetics

Background:

  • Ultraviolet B (UVB) radiation causes DNA photoproducts, which are mutagenic and impair epidermal cell function.
  • Spironolactone (SP), a mineralocorticoid and androgen receptor antagonist, inhibits UV photoproduct removal by promoting degradation of the DNA repair protein XPB.

Purpose of the Study:

  • To investigate the effects of spironolactone (SP) on DNA repair mechanisms in human skin cells and explants.
  • To determine if SP impacts the removal of UVB-induced DNA damage and subsequent cellular responses.

Main Methods:

  • Experiments were conducted using normal human keratinocytes in vitro and human skin explants ex vivo.
  • The study assessed XPB protein levels, UV photoproduct removal, and ATR/ATM DNA damage kinase signaling activation following UVB exposure.

Main Results:

  • Spironolactone (SP) rapidly depleted XPB protein in both keratinocytes and skin explants.
  • SP abrogated UV photoproduct removal and ATR/ATM kinase signaling activation in response to UVB.
  • These effects correlated with increased mutagenesis and cell death, and were specific to SP, not its metabolites or eplerenone.

Conclusions:

  • Spironolactone (SP) impairs UVB DNA damage response pathways by depleting XPB protein in human skin.
  • SP may increase UVB-induced mutagenesis and skin cancer risk in individuals.
  • This study provides a model for investigating XPB's role in skin's UVB DNA damage response.

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