HYDROCHLOROTHIAZIDE WAS NOT ASSOCIATED WITH PHOTOSENSITIVE OR PHOTOTOXIC REACTIONS AND DNA-DAMAGE IN VIVO AND IN VITRO (THE HCTOX-STUDY)

Objective: Pharmacoepidemiologic studies associated the use of HCT with an increased risk of skin cancer, resulting in a decrease of HCT prescriptions, in turn leading to worsening of blood pressure therapy in a significant proportion of patients. However, whether HCT causes skin cancer remains elusive. Hence, we aimed to examine the photosensitive and phototoxic potential of HCT in vivo in a randomized, placebo‐controlled trial. To further enlighten the pathophysiologic mechanisms of carcinogenesis and phototoxicity caused by HCT in vitro, we conducted a series of laboratory experiments. Design and method: A randomized, double‐blind, placebo‐controlled clinical trial to assess the phototoxic properties of HCT was conducted, assigning 30 healthy normotensive adult volunteers in a 2:1 ratio to either HCT 25 mg daily or placebo once daily for 15 days. The skin photosensitivity by phototesting, office blood pressure, serum 25‐hydroxyvitamin D (25(OH)D) status and urinary excretion of thymidine‐dimers, i.e. cyclobutan‐dimers by ultra‐high‐performance liquid chromatography‐high resolution mass spectrometry (UHPLC‐HRMS) following whole‐body irradiation were assessed. To further assess the pathophysiologic mechanisms of possibly HCT induced photosensitivity, human keratinocytes (HaCaT) were incubated with HCT and then irradiated with UV‐B radiation (311 nm one burst of 100 J/cm2). rt‐PCR‐testing and western blots were performed to analyze reactive oxygen species, inflammation, and carcinogenesis. Results: All 30 participants were adherent to the protocol, which was confirmed by UHPLC‐HRMS analysis of serum and plasma. Skin photosensitivity to exposure of UV‐A and UV‐B radiation did not change in both groups (HCT vs. placebo: MED‐UVB change 0.0 J/cm2 vs. 0.2 J/cm2; p = 0.06). No thymidinedimers were detectable in either group. Systolic blood pressure decreased in both groups (‐5.2 mmHg vs. 5.4 mmHg; p = 0.94), as did diastolic blood pressure (‐4.3 mmHg vs. ‐1.9 mmHg; p = 0.34). Serum 25(OH)D increased in both groups (3.1 ng/ml vs. 1.2 ng/ml; p = 0.52). HCT in combination with a single high‐intensity bursts of UV‐B radiation was not associated with increased expression of inflammatory proteins, chronic inflammation and reactive oxygen species. Conclusions: HCT was not associated with increased photosensitivity for UV‐A or UV‐B radiation in healthy volunteers. Moreover, no relevant DNA‐damages as measured by UHPLC‐HRMS were detectable in either group. The combination of HCT treatment and a single burst of UV‐B did not increase inflammatory markers. HCT appeared to be safe in healthy volunteers and was not associated with photosensitivity or DNA‐damages in vivo. (Figure Presented).