Pharmaceutical Research

, Volume 26, Issue 2, pp 449–458 | Cite as

Cellular Phototoxicity Evoked Through the Inhibition of Human ABC Transporter ABCG2 by Cyclin-dependent Kinase Inhibitors In vitro

  • Ran An
  • Yuichiro Hagiya
  • Ai Tamura
  • Shanshan Li
  • Hikaru Saito
  • Daisuke Tokushima
  • Toshihisa Ishikawa
Research Paper



The physiological importance of the human ATP-binding cassette (ABC) transporter ABCG2 has been recognized with regard to porphyrin-mediated photosensitivity. Functional impairment owing to inhibition of ABCG2 by drugs or its genetic polymorphisms may lead to the disruption of porphyrin homeostasis, which in turn causes cellular toxicity.

Materials and Methods

We evaluated the impact on photosensitivity of the inhibition by cyclin-dependent kinase (CDK) inhibitors of ABCG2 function. For this purpose, we established new methods for photosensitivity assays by using Flp-In-293 cells and plasma membrane vesicles prepared from Sf9 insect cells. With the new methods, we subsequently tested CDK inhibitors, i.e., purvalanol A, WHI-P180, bohemine, roscovitine, and olomoucine.


Among CDK inhibitors tested, purvalanol A was found to be the most potent inhibitor (IC50 = 3.5 μM) for ABCG2-mediated hematoporphyrin transport. At a concentration of 2.5 μM, it evoked the photosensitivity of ABCG2-expressing Flp-In-293 cells treated with pheophorbide a. WHI-P180 moderately inhibited ABCG2 function, exhibiting weak phototoxicity. In contrast, the phototoxicity of bohemine, roscovitine, and olomoucine were minimal in our assay system.


It is suggested that the planar structure is an important factor for interactions with the active site of ABCG2. The present study provides a new approach to studying drug-induced phototoxicity in vitro.


ABCG2 (BCRP/MXR) cyclin-dependent kinase inhibitor pheophorbide a phototoxicity porphyrin 



ATP-binding cassette


breast cancer resistance protein


cyclin-dependent kinase


Dulbecco’s modified Eagle’s medium


ethylenediaminetetraacetic acid


epidermal growth factor receptor


ethyleneglycol-bis(2-aminoethyl)-N,N,N′,N′-tetracetic acid




fetal calf serum


2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethanesulfonic acid


highest occupied molecular orbital


concentration leading to a 50%-inhibition


Michaelis–Menten constant


mitoxantrone resistance


molecular orbital


quantitative structure-activity relationship





This study was supported, in part, by the NEDO International Joint Research Grant program “International standardization of functional analysis technology for genetic polymorphisms of drug transporters” and research grants (No. 18201041 and No. 19659136) from the Japanese Society for the Promotion of Science (JSPS). Ai Tamura and Hikaru Saito are JSPS Research Fellows.


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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ran An
    • 1
  • Yuichiro Hagiya
    • 1
  • Ai Tamura
    • 1
  • Shanshan Li
    • 1
  • Hikaru Saito
    • 1
  • Daisuke Tokushima
    • 2
  • Toshihisa Ishikawa
    • 1
  1. 1.Department of Biomolecular Engineering, Graduate School of Bioscience and BiotechnologyTokyo Institute of TechnologyYokohamaJapan
  2. 2.NEC CorporationTokyoJapan

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