Voriconazole N-oxide and its ultraviolet B photoproduct sensitize keratinocytes to ultraviolet 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.


OBJECTIVE
To determine the photochemistry and photobiology of voriconazole and its major hepatic metabolite, voriconazole N-oxide.


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.
Department of Dermatology, University of California, San Francisco, CA, U.S.A.|Dermatology Research Unit, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA, 94121, U.S.A.
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Department of Dermatology, University of California, San Francisco, CA, U.S.A.|Dermatology Research Unit, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA, 94121, U.S.A.
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D000935:Antifungal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013053:Spectrophotometry; D014466:Ultraviolet Rays; D065819:Voriconazole / Q000494:pharmacology*
D000935:Antifungal Agents; D017382:Reactive Oxygen Species; C024829:8-hydroxyguanine; D006147:Guanine; D065819:Voriconazole