Assessing phototoxic drug properties of hydrochlorothiazide using human skin biopsies

Area of Science:

• Dermatology
• Photobiology
• Molecular Biology

Background:

• Hydrochlorothiazide (HCT) is linked to increased non-melanoma skin cancer risk following UV exposure.
• The specific cellular and molecular mechanisms driving this association are not fully understood.
• Existing research often relies on animal models, which may not accurately reflect human responses.

Purpose of the Study:

• To establish a human skin model for evaluating the photocarcinogenic potential of hydrochlorothiazide (HCT).
• To investigate the molecular responses of human skin to HCT combined with UVA or UVB irradiation.
• To provide a human-relevant model for drug safety assessment, reducing reliance on animal testing.

Main Methods:

• Human skin biopsies were treated with HCT.
• Biopsies were exposed to controlled doses of UVA or UVB radiation.
• Key molecular markers including p53, MDM2, DNA damage, and inflammatory genes were analyzed.

Main Results:

• Low-dose UVA with HCT activated the p53-MDM2 axis, unlike in controls.
• High-dose UVA with HCT induced DNA damage and inflammation.
• UVB induced DNA damage, p53 activation, and inflammation in both HCT-treated and untreated skin.

Conclusions:

• HCT-treated human skin exhibits UV-dependent activation of the p53-MDM2 pathway, DNA damage, and inflammatory responses.
• These findings suggest a mechanism by which HCT may contribute to skin carcinogenesis.
• The developed human skin model offers a valuable, species-specific alternative for drug phototoxicity and carcinogenicity testing.