Scholarlink

<p>The diuretic drug hydrochlorothiazide (HCT) is associated with an increased risk of non-melanoma skin cancer upon UV exposure. The underlying cellular and molecular mechanisms behind this association remain elusive. Herein, a human skin model to assess the photocarcinogenic effects of HCT is established. Skin biopsies collected from human body donors are treated with HCT and irradiated with 300 mJ/cm<sup>2</sup> low dose UVA or UVB or with 5 J/cm<sup>2</sup> high dose UVA. In HCT-treated biopsies but not in control, low dose UVA irradiation results in activation and nuclear translocation of the tumor-suppressor protein p53 accompanied by an upregulated gene expression of p53-negative regulator <i>MDM2</i>. High dose UVA additionally provokes DNA damage and initiation of pro-inflammatory gene expression. In contrast, UVB induces pronounced DNA damage, p53 protein activation, gene expression of <i>MDM2</i> and inflammatory marker genes in both HCT-treated biopsies and untreated control. In summary, in HCT-treated skin biopsies, activation of the p53-MDM2 axis, induction of DNA damage, and inflammatory response depends on UVA-dosage and may influence skin carcinogenesis over time. This human model eliminates the need for animal testing and mitigates species difference, offering a valuable tool for future drug development and safety testing.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Assessing phototoxic drug properties of hydrochlorothiazide using human skin biopsies

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月6日

查看全文
  • Mathias Hohl,
  • Felix Götzinger,
  • Simone Jäger,
  • Lea Wagmann,
  • Mert Tokcan,
  • Thomas Tschernig,
  • Jörg Reichrath,
  • Jan M. Federspiel,
  • Peter Boor,
  • Markus R. Meyer,
  • Felix Mahfoud,
  • Michael Böhm

摘要

The diuretic drug hydrochlorothiazide (HCT) is associated with an increased risk of non-melanoma skin cancer upon UV exposure. The underlying cellular and molecular mechanisms behind this association remain elusive. Herein, a human skin model to assess the photocarcinogenic effects of HCT is established. Skin biopsies collected from human body donors are treated with HCT and irradiated with 300 mJ/cm2 low dose UVA or UVB or with 5 J/cm2 high dose UVA. In HCT-treated biopsies but not in control, low dose UVA irradiation results in activation and nuclear translocation of the tumor-suppressor protein p53 accompanied by an upregulated gene expression of p53-negative regulator MDM2. High dose UVA additionally provokes DNA damage and initiation of pro-inflammatory gene expression. In contrast, UVB induces pronounced DNA damage, p53 protein activation, gene expression of MDM2 and inflammatory marker genes in both HCT-treated biopsies and untreated control. In summary, in HCT-treated skin biopsies, activation of the p53-MDM2 axis, induction of DNA damage, and inflammatory response depends on UVA-dosage and may influence skin carcinogenesis over time. This human model eliminates the need for animal testing and mitigates species difference, offering a valuable tool for future drug development and safety testing.