K Ona1,2, D H Oh1,2. 1. Department of Dermatology, University of California, San Francisco, CA, U.S.A. 2. Dermatology Research Unit, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA, 94121, U.S.A.
Abstract
BACKGROUND: The antifungal agent, voriconazole, is associated with phototoxicity and photocarcinogenicity. Prior work has indicated that voriconazole and its hepatic N-oxide metabolite do not sensitize keratinocytes to ultraviolet B (UVB). Clinical observations have suggested that ultraviolet A (UVA) may be involved. OBJECTIVES: To determine the photochemistry and photobiology of voriconazole and its major hepatic metabolite, voriconazole N-oxide. MATERIALS AND METHODS: Voriconazole and voriconazole N-oxide were spectrophotometrically monitored following various doses of UVB. Cultured human keratinocytes were treated with parental drugs or with their UVB photoproducts, and survival following UVA irradiation was measured by thiazolyl blue metabolism. Reactive oxygen species (ROS) and 8-oxoguanine were monitored by fluorescence microscopy. RESULTS: Voriconazole and voriconazole N-oxide have varying UVB absorption but do not acutely sensitize cultured human keratinocytes following UVB exposure. However, sustained UVB exposures produced notable dose- and solvent-dependent changes in the absorption spectra of voriconazole N-oxide, which in aqueous solution acquires a prominent UVA absorption band, suggesting formation of a discrete photoproduct. Neither the parental drugs nor their photoproducts sensitized cells to UVB although all but voriconazole N-oxide were moderately toxic to cells in the dark. Notably, both voriconazole N-oxide and its UVB photoproduct, but not voriconazole or its photoproduct, additionally sensitized cells to UVA by greater than three-fold relative to controls in association with UVA-induced ROS and 8-oxoguanine levels. CONCLUSIONS: Voriconazole N-oxide and its UVB-photoproduct act as UVA-sensitizers that generate ROS and that produce oxidative DNA damage. These results suggest a mechanism for the phototoxicity and photocarcinogenicity observed with voriconazole treatment. Published 2015. This article is a U.S. Government work and is in the public domain in the U.S.A.
BACKGROUND: The antifungal agent, voriconazole, is associated with phototoxicity and photocarcinogenicity. Prior work has indicated that voriconazole and its hepatic N-oxide metabolite do not sensitize keratinocytes to ultraviolet B (UVB). Clinical observations have suggested that ultraviolet A (UVA) may be involved. OBJECTIVES: To determine the photochemistry and photobiology of voriconazole and its major hepatic metabolite, voriconazole N-oxide. MATERIALS AND METHODS:Voriconazole and voriconazole N-oxide were spectrophotometrically monitored following various doses of UVB. Cultured human keratinocytes were treated with parental drugs or with their UVB photoproducts, and survival following UVA irradiation was measured by thiazolyl blue metabolism. Reactive oxygen species (ROS) and 8-oxoguanine were monitored by fluorescence microscopy. RESULTS:Voriconazole and voriconazole N-oxide have varying UVB absorption but do not acutely sensitize cultured human keratinocytes following UVB exposure. However, sustained UVB exposures produced notable dose- and solvent-dependent changes in the absorption spectra of voriconazole N-oxide, which in aqueous solution acquires a prominent UVA absorption band, suggesting formation of a discrete photoproduct. Neither the parental drugs nor their photoproducts sensitized cells to UVB although all but voriconazole N-oxide were moderately toxic to cells in the dark. Notably, both voriconazole N-oxide and its UVB photoproduct, but not voriconazole or its photoproduct, additionally sensitized cells to UVA by greater than three-fold relative to controls in association with UVA-induced ROS and 8-oxoguanine levels. CONCLUSIONS:Voriconazole N-oxide and its UVB-photoproduct act as UVA-sensitizers that generate ROS and that produce oxidative DNA damage. These results suggest a mechanism for the phototoxicity and photocarcinogenicity observed with voriconazole treatment. Published 2015. This article is a U.S. Government work and is in the public domain in the U.S.A.
Authors: M D'Errico; M Teson; A Calcagnile; L Proietti De Santis; O Nikaido; E Botta; G Zambruno; M Stefanini; E Dogliotti Journal: Cell Death Differ Date: 2003-06 Impact factor: 15.828
Authors: D M Saunte; F Simmel; N Frimodt-Moller; L B Stolle; E L Svejgaard; M Haedersdal; C Kloft; M C Arendrup Journal: Antimicrob Agents Chemother Date: 2007-06-18 Impact factor: 5.191
Authors: Jennifer T Huang; Carrie C Coughlin; Elena B Hawryluk; Kristen Hook; Stephen R Humphrey; Lacey Kruse; Leslie Lawley; Hasan Al-Sayegh; Wendy B London; Ashfaq Marghoob; Thuy L Phung; Elena Pope; Pedram Gerami; Birgitta Schmidt; Sarah Robinson; Diana Bartenstein; Eman Bahrani; Meera Brahmbhatt; Lily Chen; Ellen Haddock; Danny Mansour; Julie Nguyen; Tom Raisanen; Gary Tran; Kate Travis; Zachary Wolner; Lawrence F Eichenfield Journal: J Pediatr Date: 2019-05-15 Impact factor: 4.406
Authors: Lawrence F Kuklinski; Shufeng Li; Margaret R Karagas; Wen-Kai Weng; Bernice Y Kwong Journal: J Am Acad Dermatol Date: 2017-08-02 Impact factor: 11.527
Authors: Vivian Lee; Michael D Gober; Hasan Bashir; Conor O'Day; Ian A Blair; Clementina Mesaros; Liwei Weng; Andrew Huang; Aaron Chen; Rachel Tang; Vince Anagnos; JiLon Li; Sophie Roling; Emilija Sagaityte; Andrew Wang; Chenyan Lin; Christopher Yeh; Cem Atillasoy; Christine Marshall; Tzvete Dentchev; Todd Ridky; John T Seykora Journal: Exp Dermatol Date: 2019-10-29 Impact factor: 3.960
Authors: Kristin Bibee; Andrew Swartz; Shaum Sridharan; Cornelius H L Kurten; Charles B Wessel; Heath Skinner; Dan P Zandberg Journal: Oral Oncol Date: 2020-02-14 Impact factor: 5.337
Authors: Elisabeth A George; Navya Baranwal; Jae H Kang; Abrar A Qureshi; Aaron M Drucker; Eunyoung Cho Journal: Cancers (Basel) Date: 2021-05-12 Impact factor: 6.639