Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice
Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice
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DOI：
10.1111/php.12972
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发表时间：
2018-09-01
影响因子：
3.3
通讯作者：
Nishigori, Chikako
中科院分区：
文献类型：
--
作者：
Kunisada, Makoto;Yamano, Nozomi;Nishigori, Chikako
伏立康唑是一种抗真菌剂，用作预防措施，特别是在免疫功能低下的患者中。然而，也有一些关于其不良反应的报道，即光敏性与强烈的炎症性皮疹和随后的皮肤癌发展。为了评估光敏药物伏立康唑和氢氯噻嗪（HCTZ）对增强紫外线诱导的炎症反应和紫外线诱导的肿瘤发生的作用，我们利用xpa敲除小鼠，这种小鼠DNA修复缺陷，比野生型小鼠更容易受到紫外线诱导的炎症和肿瘤的发生。与载体组或hctz组相比，在宽带UVB暴露前给予伏立康唑显著上调多种炎症细胞因子。在xpa基因敲除小鼠中，伏立康唑与慢性UVB暴露在一起产生的皮肤肿瘤数量明显高于HCTZ或对照。此外，利用xpa基因敲除小鼠的胚胎成纤维细胞对uvb诱导的DNA损伤进行研究发现，在紫外线暴露期间，伏立康唑代谢物n -氧化物（voriconazole N-oxide）处理的细胞中，8-氧-7,8-二氢鸟嘌呤水平显著提高。这些数据提示伏立康唑加uvb诱导的炎症反应可能与伏立康唑诱导的皮肤光瘤发生有关。
Voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide (HCTZ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis, we utilized Xpa-knockout mice, which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice. Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle- or HCTZ-administered groups. Voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa-knockout mice. Furthermore, the investigation of UVB-induced DNA damage using embryonic fibroblasts of Xpa-knockout mice revealed a significantly higher 8-oxo-7,8-dihydroguanine level in cells treated with voriconazole N-oxide, a voriconazole-metabolite during UV exposure. The data suggest that voriconazole plus UVB-induced inflammatory response may be related to voriconazole-induced skin phototumorigenesis.