oriconazole does not Potentiate Photo Damage from UVB Exposure

Abstract

Voriconazole is an effective anti-fungal triazole commonly used in bone marrow and solid organ transplant recipients. However, reports of accelerated development of aggressive squamous cell carcinomas in immunocompromised patients are documented following voriconazole use. It is hypothesized that voriconazole or its primary N-oxide metabolite, voricinazole-N-oxide increases keratinocyte susceptibility via UV-mediated cell damage. We aimed to investigate whether voriconazole or voriconazole-N-oxide potentiate cell death after UVB irradiation in vitro.Both compounds absorb UVB but voriconazole exhibited weak emission while voriconazole-N-oxide showed no detectable emission in UVA. Exposure of different skin cell lines to these compounds did not show significant reduction in cell survival and regardless whether the cells were exposed to the drugs before or after UVB irradiation. However, in primary human keratinocytes, both drugs caused a small increase in cell survival following drug incubation and UVB irradiation. This is the first report documenting the effect of voriconazole and voriconazole-N-oxide in relation to UVBassociated cell death in vitro.

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

“…In contrast, VNO exhibited minimal toxicity in the dark but VNO′ exhibited toxicity, resulting in a loss in viability of 50% of cells. Similar to our prior observations, neither voriconazole nor VNO sensitized keratinocytes to UVB doses up to 700 J m −2 (70 mJ cm −2 ) relative to diluent‐treated controls, as measured by the thiazolyl blue assay 5 days following UVB (Fig. c).…”

“…We find that, while voriconazole and VNO and their UVB‐generated photoproducts all exhibit some toxicity to cells in the dark, none further sensitizes cells to UVB exposure. This result is consistent with our prior report that voriconazole and VNO alone do not sensitize cells to UVB exposure, and further suggests that neither these drugs nor their UVB photoproducts impair nucleotide excision repair of UVB‐induced DNA lesions. Despite some clinical similarities in skin appearance of patients receiving chronic voriconazole to patients with xeroderma pigmentosum, in whom deficiencies in nucleotide excision repair lead to significant UVB sensitization (Fig.…”

“…Because keratinocytes also express many of the same cytochrome P450 enzymes, it is possible that VNO, rather than solely travelling from liver to skin, is locally generated in skin epidermis where voriconazole appears to accumulate . However, our initial studies have shown that neither voriconazole nor VNO sensitize cells to UVB in vitro , suggesting that these molecules themselves are not direct UVB photosensitizing agents …”

“…Voriconazole itself has relatively weak absorbance in the UVB (290–320 nm) and UVA (320–400 nm) spectral regions that are relevant for terrestrial solar exposure, so speculation has focused on voriconazole N‐oxide (VNO), the major hepatic metabolite of voriconazole, which constitutes 72% of circulating metabolites and possesses stronger UVB and UVA absorbance (Fig. ) . Cytochrome P450 enzymes, principally CYP2C19 and CYP3A4, metabolize voriconazole to the N‐oxide as well as hydroxyl derivatives, and CYP2C19 polymorphisms have been speculated to be one factor governing the risk of phototoxicity .…”

Inflammation Due to Voriconazole‐induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa‐knockout Mice

“…1a). These results indicate that the responsible wavelength for the enhancement of UV-induced cytokine expression by these drugs fall into the 275-390 nm, which is consistent with the absorption spectrum of HCTZ or voriconazole and its major hepatic metabolite, VN-oxide (16,17). Furthermore, we studied whether there was a possibility that voriconazole itself, in the absence of UV, was involved in some effects on the upregulation of cytokines.…”