In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs
In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs
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DOI：
10.2133/dmpk.22.428
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发表时间：
2007-01-01
影响因子：
2.1
通讯作者：
Ishikawa, Toshihisa
中科院分区：
文献类型：
--
作者：
Tamura, Ai;Onishi, Yuko;Ishikawa, Toshihisa
由于卟啉被认为是ATP结合盒（ABC）转运蛋白ABCG 2的内源性底物，因此假设由于遗传多态性或药物对ABCG 2的抑制而导致的功能障碍可能会导致细胞卟啉稳态的破坏。在本研究中，我们表达了ABCG 2遗传变体，即，V12 M、Q141 K、S441 N和F489 L以及野生型（WT）在Flp-In-293细胞中的表达以检验该假设。表达S441 N和F489 L变体的细胞表现出高水平的细胞内积累的脱镁叶绿酸a和光敏性，当这些细胞与脱镁叶绿酸a孵育并用可见光照射时。为了进一步阐明ABCG 2在细胞卟啉稳态中的意义，我们通过新的荧光显微镜技术观察了卟啉和脱镁叶绿酸a的细胞积累和区室化，并发现在表达ABCG 2 WT、V12 M或Q141 K的Flp-In-293细胞中，卟啉和脱镁叶绿酸a在细胞质区室中的积累维持在低水平。然而，当ABCG 2被伊马替尼或新生霉素抑制时，这些细胞变得对光敏感。基于这些结果，强烈建议某些遗传多态性和/或药物对ABCG 2的抑制可以增加光敏性的潜在风险。
Since porphyrins are regarded as endogenous substrates for the ATP-binding cassette (ABC) transporter ABCG2, it is hypothesized that functional impairment owing to genetic polymorphisms or inhibition of ABCG2 by drugs may result in a disruption of cellular porphyrin homeostasis. In the present study, we expressed ABCG2 genetic variants, i.e., V12M, Q141K, S441N, and F489L, as well as the wild type (WT) in Flp-In-293 cells to examine the hypothesis. Cells expressing S441N and F489L variants exhibited high levels of both cellularly accumulated pheophorbide a and photosensitivity, when those cells were incubated with pheophorbide a and irradiated with visible light. To further elucidate the significance of ABCG2 in cellular porphyrin homeostasis, we observed cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new fluorescence microscopy technology, and found that accumulation of porphyrin and pheophorbide a in the cytoplasm compartment was maintained at low levels in Flp-In-293 cells expressing ABCG2 WT, V12M, or Q141K. When ABCG2 was inhibited by imatinib or novobiocin, however, those cells became sensitive to light. Based on these results, it is strongly suggested that certain genetic polymorphisms and/or inhibition of ABCG2 by drugs can enhance the potential risk of photosensitivity.