Stress Responses of Human Dermal Fibroblasts Exposed to Zinc Pyrithione
Abstract
Zinc pyrithione is used as a topical agent in a range of medicinal and cosmetic applications. Despite its extensive use and reported beneficial effects in treatment of various dermal problems, its potential toxicity towards skin cells remains relatively underexplored. In this work we investigated effects of nM zinc pyrithione on cell stress response pathways of primary human skin fibroblasts during 24h of exposure. We demonstrate that zinc pyrithione-induced cytotoxity in dermal fibroblasts is dose-dependent and it associates with increased intracellular zinc concentrations and activated stress response pathways including p53 and stress kinase p38. Higher zinc pyrithione concentrations (500nM and above) stimulate oxidative stress and moderate DNA damage which occur in the presence of activated p38 kinase. Cells further upregulate the expression of p53 which increases its transcriptional activity while mitogenic signaling exemplified by mTOR (mammalian target of rapamycin) expression is suppressed and these steps lead to mitochondrial, caspase-dependent apoptosis. Conversely, lower zinc concentrations (125nM) fail to induce oxidative stress and significant DNA damage; however, treated cells still activate p38 and upregulate the expression and transcriptional activity of p53 and its target gene p21 as well as the expression of p16 in the presence of active mTOR pathway and a changed DNA methylation pattern. The end result is premature senescence phenotype. Specific pharmacological inhibitors as well as gene knockdown technology prove that an interaction between p38, p53 and mTOR might be responsible for these observed endpoints. Taken together, exposure of dermal fibroblasts to varying concentrations of zinc pyrithione may result in either cell death-apoptosis or cellular premature senescence which attests to the ability of this compound to affect this type of cells in an in vitro model system.
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The structural and functional roles of zinc, selenium, magnesium, copper, and manganese are crucial for antioxidant defence.
“Concerning the latter, the structural and functional roles of a few minerals such as zinc (Zn), selenium (Se), magnesium (Mg) copper (Cu) and manganese (Mn) is crucial (Table 5) [409,410,411,412,413,414,415,416,417,418,419,420].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [410]
In a colon cancer cell line and dermal fibroblasts, zinc dysregulation promotes cellular senescence by activating stress response and pro-apoptosis pathways.
“For instance, in a colon cancer cell line [409] and dermal fibroblasts [410], Zn dysregulation promoted cellular senescence activating stress response and pro-apoptosis pathways.”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [410]
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- Authors
- Rudolf, E., & Cervinka, M.
- Affiliations
- Charles University (CZ)
- Corresponding author
- Rudolf, Emil
- ORCID
- Rudolf, Emil
- Venue
- Toxicology Letters
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 204
- Issue
- 2-3
- Pages
- 164-173
- ISSN
- 0378-4274 (ISSN-L)
- OpenAlex
- W2087495130
- Cited by
- 36
- References
- 41
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education of Czech Republic Research Project (MSM 0021620820)
- Topics
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- zinc pyrithione, dermal fibroblasts, cytotoxicity, oxidative stress, DNA damage, p53, p38 MAPK, mTOR, apoptosis, premature senescence, DNA methylation, p21, p16, intracellular zinc, topical agents
- MeSH terms
- Cells, Cultured, DNA, Fibroblasts, Humans, Keratolytic Agents, Organometallic Compounds, Pyridines, Skin, Stress, Physiological, Tumor Suppressor Protein p53, Cellular Senescence, Apoptosis, Oxidative Stress, Mitogen-Activated Protein Kinases, Cell Proliferation
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