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

伏立康唑（VRCZ）诱导UV相关皮肤癌的发展。VRCZ诱发皮肤肿瘤的临床研究（综述了VRCZ诱发的皮肤肿瘤的临床研究，并对VRCZ诱发的光化性角化病（AK）与普通AK进行了组织病理学比较）表明，VRCZ在一定的免疫抑制条件下能强烈诱发角质形成细胞（KC）的肿瘤形成，其肿瘤发生并非单纯的光敏性所致。在体外实验中，我们发现VRCZ代谢产物加上UVA产生活性氧和由此产生的表皮DNA损伤，但并没有诱导大量的细胞凋亡的KC。此外，VRCZ本身刺激芳香烃受体（AhR）和上调考克斯-2，这是一个关键的酶，促进紫外线相关的肿瘤，在一个经典的（基因组）pathway AhR-ARNT依赖的方式。我们的研究结果表明，VRCZ主要促进肿瘤的发展预先存在的紫外线损伤KCs在临床设置中，而VRCZ代谢产物的光毒性部分可能参与在起始阶段。

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.