Document Detail


Zinc pyrithione impairs zinc homeostasis and upregulates stress response gene expression in reconstructed human epidermis.
MedLine Citation:
PMID:  21424779     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Zinc ion homeostasis plays an important role in human cutaneous biology where it is involved in epidermal differentiation and barrier function, inflammatory and antimicrobial regulation, and wound healing. Zinc-based compounds designed for topical delivery therefore represent an important class of cutaneous therapeutics. Zinc pyrithione (ZnPT) is an FDA-approved microbicidal agent used worldwide in over-the-counter topical antimicrobials, and has also been examined as an investigational therapeutic targeting psoriasis and UVB-induced epidermal hyperplasia. Recently, we have demonstrated that cultured primary human skin keratinocytes display an exquisite sensitivity to nanomolar ZnPT concentrations causing induction of heat shock response gene expression and poly(ADP-ribose) polymerase (PARP)-dependent cell death (Cell Stress Chaperones 15:309-322, 2010). Here we demonstrate that ZnPT causes rapid accumulation of intracellular zinc in primary keratinocytes as observed by quantitative fluorescence microscopy and inductively coupled plasma mass spectrometry (ICP-MS), and that PARP activation, energy crisis, and genomic impairment are all antagonized by zinc chelation. In epidermal reconstructs (EpiDerm™) exposed to topical ZnPT (0.1-2% in Vanicream™), ICP-MS demonstrated rapid zinc accumulation, and expression array analysis demonstrated upregulation of stress response genes encoding metallothionein-2A (MT2A), heat shock proteins (HSPA6, HSPA1A, HSPB5, HSPA1L, DNAJA1, HSPH1, HSPD1, HSPE1), antioxidants (SOD2, GSTM3, HMOX1), and the cell cycle inhibitor p21 (CDKN1A). IHC analysis of ZnPT-treated EpiDerm™ confirmed upregulation of Hsp70 and TUNEL-positivity. Taken together our data demonstrate that ZnPT impairs zinc ion homeostasis and upregulates stress response gene expression in primary keratinocytes and reconstructed human epidermis, activities that may underlie therapeutic and toxicological effects of this topical drug.
Authors:
Sarah D Lamore; Georg T Wondrak
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-22
Journal Detail:
Title:  Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine     Volume:  24     ISSN:  1572-8773     ISO Abbreviation:  Biometals     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-08-30     Completed Date:  2011-12-23     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  9208478     Medline TA:  Biometals     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  875-90     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cells, Cultured
Dose-Response Relationship, Drug
Epidermis / cytology,  drug effects*,  metabolism
HSP70 Heat-Shock Proteins / genetics*
Homeostasis / drug effects*
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Keratinocytes / cytology,  drug effects,  metabolism
Organometallic Compounds / pharmacology*
Oxidative Stress / drug effects*,  genetics
Pyridines / pharmacology*
Structure-Activity Relationship
Up-Regulation / drug effects*
Zinc / metabolism*
Grant Support
ID/Acronym/Agency:
CA023074/CA/NCI NIH HHS; ES007091/ES/NIEHS NIH HHS; ES06694/ES/NIEHS NIH HHS; P30 ES006694/ES/NIEHS NIH HHS; R01 CA122484/CA/NCI NIH HHS; R01CA122484/CA/NCI NIH HHS; T32 ES007091/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/HSP70 Heat-Shock Proteins; 0/Organometallic Compounds; 0/Pyridines; J41CSQ7QDS/Zinc; R953O2RHZ5/pyrithione zinc

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