抗真菌剤ボリコナゾールによる芳香族炭化水素受容体を介した皮膚癌進展機序の解明

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Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown.Clinical studies (VRCZ-induced skin tumors were clinically summarized, and VRCZ-induced actinic keratosis (AK) were histopathologically compared with ordinary AK) suggested that VRCZ can strongly evoke the tumor formation of keratinocytes (KC)s under a certain immunocompromised condition and its tumorigenesis is not simply caused by photosensitivity. In vitro, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in KCs. Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway.Our findings suggest that VRCZ primarily promotes the tumor development of preexisted UV-damaged KCs in clinical settings, while the phototoxic moieties of VRCZ metabolites may participate in the initiation phase.