Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro.

Abstract

PURPOSE:

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.

RESULTS:

Among CDK inhibitors tested, purvalanol A was found to be the most potent inhibitor (IC50=3.5 microM) for ABCG2-mediated hematoporphyrin transport. At a concentration of 2.5 microM, 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.

CONCLUSIONS:

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.

• Authors: Ran An, Yuichiro Hagiya, Ai Tamura, Shanshan Li, Hikaru Saito, Daisuke Tokushima, Toshihisa Ishikawa
• Journal: Pharmaceutical research (Pharm Res) Vol. 26 Issue 2 Pg. 449-58 (Feb 2009) ISSN: 0724-8741 [Print] United States
• PMID: 18841444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Hematoporphyrins
• Neoplasm Proteins
• Photosensitizing Agents
• Protein Kinase Inhibitors
• Purines
• Quinazolines
• WHI P180
• bohemine
• Roscovitine
• Chlorophyll
• olomoucine
• Cyclin-Dependent Kinases
• pheophorbide a
• Kinetin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, metabolism)
• Animals
• Cell Line
• Cell Membrane (drug effects, metabolism)
• Cell Survival (drug effects)
• Chlorophyll (analogs & derivatives, toxicity)
• Cyclin-Dependent Kinases (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Hematoporphyrins (metabolism)
• Humans
• Kinetin (pharmacology)
• Models, Molecular
• Molecular Conformation
• Molecular Structure
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Photosensitizing Agents (toxicity)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Purines (pharmacology)
• Quantitative Structure-Activity Relationship
• Quinazolines (pharmacology)
• Roscovitine
• Spodoptera
• Transfection