title: In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs.
abstract: 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.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Tamura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Onishi
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.forename: Shoko
authors.initials: S
authors.lastname: Koshiba
authors.forename: Kanako
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hoshijima
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kometani
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Matsubara
authors.forename: Kenta
authors.initials: K
authors.lastname: Mikuriya
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: 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
chemical_list: 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