Abstract 641 Hydrochlorothiazide did not lead to phototoxic reactions and DNA-damage in healthy volunteers

Purpose:
Pharmacoepidemiologic studies associated the use of Hydrochlorothiazide (HCTZ) with an increased risk of skin cancer (especially non-melanoma skin cancer), resulting in a decrease of HCTZ prescriptions, which in turn lead to worsening of blood pressure therapy in a significant proportion of patients. However, whether HCTZ causes skin cancer remains elusive. Hence, we aimed to examine the photosensitive potential of HCTZ in vivo in a randomized, placebo-controlled trial. To further enlighten the pathophysiologic mechanisms of carcinogenesis and phototoxicity caused by HCTZ in vitro, we conducted a series of laboratory experiments.

Methods:
A randomized, double-blinded, placebo-controlled clinical trial to assess the phototoxic properties of HCTZ was conducted, assigning 30 healthy normotensive adult volunteers in a 2:1 ratio to either HCTZ 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 HCTZ induced photosensitivity, human keratinocytes (HaCaT) were incubated with either Dimethyl sulfoxide (DMSO), DMSO and HCTZ or DMSO and amiodarone for one hour, and then irradiated with UV-B radiation (311 nm one burst of 100 J/cm²). rt-PCR-testing, western blots and ELISA-testing were performed to analyze reactive oxygen species, inflammation, and carcinogenesis as well as the formation of thymidine-dimers.

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 (UVB-MED: HCTZ delta = 0.0 J/cm2 vs. placebo delta =0.2 J/cm2; p=0.055). No thymidine-dimers were detected in either group.

Systolic blood pressure (SBP) decreased in both groups (HCTZ mean reduction = 5.2 mmHg vs. placebo mean reduction = 5.4 mmHg; p=0.948), as did the diastolic blood pressure (DBP) (HCTZ mean reduction = 1.9 mmHg vs. placebo mean reduction = 4.3 mmHg; p=0.346), respectively.

Serum 25(OH)D increased in both groups (HCTZ increase = 2.7 ng/ml vs. placebo increase =0.9 ng/ml; p=0.566).

HCTZ and DMSO alone did not increase the expression of inflammatory proteins (IL-6, TNFalpha) or tumor suppressor proteins (p53, p63, p73). However, HCTZ in combination with high-intensity bursts of UV-B radiation did cause increased expression of inflammatory proteins and reactive oxygen species. No adverse events related to the study medication were reported.

Conclusions:
HCTZ did not appear to significantly increase photosensitivity for UV-A or UV-B radiation in healthy volunteers compared with placebo. Moreover, no relevant DNA-damages as measured by HPLC could be detected in either group. HCTZ alone did not lead to increased inflammation, formation of reactive oxygen species, or carcinogenesis in human keratinocytes. The combination of a UV-B burst and HCTZ however, did lead to an increase in inflammatory markers.

A cumulative dose of 375 mg HCTZ appeared to be safe in healthy volunteers and did not lead to increased photosensitivity or DNA-damages in vivo.

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
Hydrochlorothiazide did not lead to phototoxic reactions and DNA-damage in healthy volunteers - the "HCTox-Study"
F. Götzinger¹, L. Lauder², D. Millenaar², M. Hohl², C. Ukena², F. Mahfoud², M. Meyer³, J. Reichrath⁴, M. Böhm²
¹Klinik für Innere Medizin III - Kardiologie, Angiologie, Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; ²Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; ³Experimentelle und klinische Toxikologie, Universität des Saarlandes, Homburg; ⁴Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum des Saarlandes, Homburg;
Purpose: Pharmacoepidemiologic studies associated the use of Hydrochlorothiazide (HCTZ) with an increased risk of skin cancer (especially non-melanoma skin cancer), resulting in a decrease of HCTZ prescriptions, which in turn lead to worsening of blood pressure therapy in a significant proportion of patients. However, whether HCTZ causes skin cancer remains elusive. Hence, we aimed to examine the photosensitive potential of HCTZ in vivo in a randomized, placebo-controlled trial. To further enlighten the pathophysiologic mechanisms of carcinogenesis and phototoxicity caused by HCTZ in vitro, we conducted a series of laboratory experiments. Methods: A randomized, double-blinded, placebo-controlled clinical trial to assess the phototoxic properties of HCTZ was conducted, assigning 30 healthy normotensive adult volunteers in a 2:1 ratio to either HCTZ 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 HCTZ induced photosensitivity, human keratinocytes (HaCaT) were incubated with either Dimethyl sulfoxide (DMSO), DMSO and HCTZ or DMSO and amiodarone for one hour, and then irradiated with UV-B radiation (311 nm one burst of 100 J/cm²). rt-PCR-testing, western blots and ELISA-testing were performed to analyze reactive oxygen species, inflammation, and carcinogenesis as well as the formation of thymidine-dimers. 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 (UVB-MED: HCTZ delta = 0.0 J/cm2 vs. placebo delta =0.2 J/cm2; p=0.055). No thymidine-dimers were detected in either group. Systolic blood pressure (SBP) decreased in both groups (HCTZ mean reduction = 5.2 mmHg vs. placebo mean reduction = 5.4 mmHg; p=0.948), as did the diastolic blood pressure (DBP) (HCTZ mean reduction = 1.9 mmHg vs. placebo mean reduction = 4.3 mmHg; p=0.346), respectively. Serum 25(OH)D increased in both groups (HCTZ increase = 2.7 ng/ml vs. placebo increase =0.9 ng/ml; p=0.566). HCTZ and DMSO alone did not increase the expression of inflammatory proteins (IL-6, TNFalpha) or tumor suppressor proteins (p53, p63, p73). However, HCTZ in combination with high-intensity bursts of UV-B radiation did cause increased expression of inflammatory proteins and reactive oxygen species. No adverse events related to the study medication were reported. Conclusions: HCTZ did not appear to significantly increase photosensitivity for UV-A or UV-B radiation in healthy volunteers compared with placebo. Moreover, no relevant DNA-damages as measured by HPLC could be detected in either group. HCTZ alone did not lead to increased inflammation, formation of reactive oxygen species, or carcinogenesis in human keratinocytes. The combination of a UV-B burst and HCTZ however, did lead to an increase in inflammatory markers. A cumulative dose of 375 mg HCTZ appeared to be safe in healthy volunteers and did not lead to increased photosensitivity or DNA-damages in vivo.
https://dgk.org/kongress_programme/jt2022/aV556.html