The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells

Sarah D. Lamore, Christopher M. Cabello, Georg T Wondrak

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The differentiated epidermis of human skin serves as an essential barrier against environmental insults from physical, chemical, and biological sources. Zinc pyrithione (ZnPT) is an FDA-approved microbicidal agent used worldwide in clinical antiseptic products, over-the-counter topical antimicrobials, and cosmetic consumer products including antidandruff shampoos. Here we demonstrate for the first time that cultured primary human skin keratinocytes and melanocytes display an exquisite vulnerability to nanomolar concentrations of ZnPT resulting in pronounced induction of heat shock response gene expression and impaired genomic integrity. In keratinocytes treated with nanomolar concentrations of ZnPT, expression array analysis revealed massive upregulation of genes encoding heat shock proteins (HSPA6, HSPA1A, HSPB5, HMOX1, HSPA1L, and DNAJA1) further confirmed by immunodetection. Moreover, ZnPT treatment induced rapid depletion of cellular ATP levels and formation of poly(ADP-ribose) polymers. Consistent with an involvement of poly(ADP-ribose) polymerase (PARP) in ZnPT-induced energy crisis, ATP depletion could be antagonized by pharmacological inhibition of PARP. This result was independently confirmed using PARP-1 knockout mouse embryonic fibroblasts that were resistant to ATP depletion and cytotoxicity resulting from ZnPT exposure. In keratinocytes and melanocytes, single-cell gel electrophoresis and flow cytometric detection of γ-H2A.X revealed rapid induction of DNA damage in response to ZnPT detectable before general loss of cell viability occurred through caspase-independent pathways. Combined with earlier experimental evidence that documents penetration of ZnPT through mammalian skin, our findings raise the possibility that this topical antimicrobial may target and compromise keratinocytes and melanocytes in intact human skin.

Original languageEnglish (US)
Pages (from-to)309-322
Number of pages14
JournalCell Stress and Chaperones
Volume15
Issue number3
DOIs
StatePublished - May 2010

Fingerprint

Heat-Shock Response
Poly(ADP-ribose) Polymerases
DNA Damage
Skin
DNA
Keratinocytes
Melanocytes
Adenosine Triphosphate
Poly Adenosine Diphosphate Ribose
Gene encoding
Local Anti-Infective Agents
Comet Assay
Consumer products
Cosmetics
pyrithione zinc
Hot Temperature
Fibroblasts
Cytotoxicity
Caspases
Heat-Shock Proteins

Keywords

  • Comet assay
  • Heat shock response
  • Keratinocyte
  • Melanocyte
  • PARP-dependent ATP depletion
  • Zinc pyrithione

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells. / Lamore, Sarah D.; Cabello, Christopher M.; Wondrak, Georg T.

In: Cell Stress and Chaperones, Vol. 15, No. 3, 05.2010, p. 309-322.

Research output: Contribution to journalArticle

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