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

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-thecounter 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.

Immunotoxicity in ascidians: Antifouling compounds alternative to organotins—IV. The case of zinc pyrithione

“…Early and late apoptosis occurred after exposure to 0.1 and 0.5 μM, respectively. This finding is in agreement with genotoxic effects observed as DNA strand breaks with a comet assay in keratinocytes of human epidermis after exposure in vitro to 0.1 μM (Lamore et al, 2010) and in the marine mussel Mytilus galloprovincialis as an amplified DNA fragmentation with the TUNEL reaction after 2 days of exposure of the gills and digestive gland samples to 0.2 μM (Marcheselli et al, 2011).…”

Antineoplastic activity of ouabain and pyrithione zinc in acute myeloid leukemia

“…Its dermatological applications include the treatment of dandruff and seborrhoeic dermatitis, and evidence suggests PZ might be beneficial for the treatment of psoriasis, eczema, ringworm, skin mycoses and atopic dermatitis. PZ reportedly perturbs zinc homeostasis (Lamore and Wondrak, 2011), and induces a DNA-damage response followed by lethal activation of poly(ADP-ribose)polymerase (Lamore et al, 2009). In AML cells, however, PZ failed to induce DNA damage (Figure 3).…”

Phytotoxicity evaluation of some commonly used shampoos using Brassica napus L.

“…Similarly, climbazole was reported to inhibit growth in Avena sativa and Brassica napus (Richter et al 2013). Zinc pyrithione (ZPT) is an active ingredient in several shampoos (Sanchez-Bayo and Goka 2005), and it can trigger a variety of responses in the cell (Lamore et al 2010). ZPT can cause cellular toxicity through an increase in copper influx as observed in the scalp fungus Malassezia globosa (Reeder et al 2011).…”