Assessing phototoxic drug properties of hydrochlorothiazide using human skin biopsies

Abstract

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 proinflammatory 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.