In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs.
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.
Tamura
Ai
A
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
Onishi
Yuko
Y
An
Ran
R
Koshiba
Shoko
S
Wakabayashi
Kanako
K
Hoshijima
Kazuyuki
K
Priebe
Waldemar
W
Yoshida
Takashi
T
Kometani
Satoshi
S
Matsubara
Takayoshi
T
Mikuriya
Kenta
K
Ishikawa
Toshihisa
T
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006706:Homeostasis; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D007313:Insecta; D008027:Light; D049990:Membrane Transport Modulators / Q000633:toxicity*; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009675:Novobiocin / Q000633:toxicity; D010787:Photosensitivity Disorders / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D017319:Photosensitizing Agents / Q000378:metabolism / Q000633:toxicity*; D010879:Piperazines / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide; D011166:Porphyrins / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity; D011794:Quercetin / Q000494:pharmacology / Q000633:toxicity; D018570:Risk Assessment; D014162:Transfection
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; D010879:Piperazines; D011166:Porphyrins; D011743:Pyrimidines; D002734:Chlorophyll; D009675:Novobiocin; D000068877:Imatinib Mesylate; D011794:Quercetin; C032623:pheophorbide a