Decreased Biosynthesis of Lung Surfactant Constituent Phosphatidylcholine Due to Inhibition of Choline Transporter by Gefitinib in Lung Alveolar Cells |
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Authors: | Naoki Ishiguro Masanobu Oyabu Toshihiro Sato Tomoji Maeda Hironobu Minami Ikumi Tamai |
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Institution: | (1) Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamasaki, Noda, Chiba 278-8510, Japan;(2) National Cancer Center Hospital East, Kashiwa, Japan |
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Abstract: | Purpose We investigated whether gefitinib, an anticancer agent, inhibits phosphatidylcholine (PC) biosynthesis and choline uptake
by alveolar epithelial type II cells.
Materials and Methods Uptake of choline and PC biosynthesis were examined in vitro, using human alveolar epithelia-derived cell line A549 and rat alveolar type (AT) II cells as models.
Results Gefitinib reduced the incorporation of 3H]choline into PC in A549 and rat ATII cells. The uptake of 3H]choline by A549 and rat ATII cells was concentration-dependent, and the Km values were 15.0 and 10–100 μM, respectively.
The uptake of 3H]choline by A549 and rat ATII cells was weakly Na+-dependent, and inhibited by hemicholinium-3. RT-PCR revealed expression of choline transporter-like protein (CTL)1 and organic
cation transporter (OCT)3 mRNAs in both cells. The choline uptake by A549 and rat ATII cells was strongly inhibited by gefitinib
with the IC50 value of 6.77 μM and 10.5 μM, respectively.
Conclusions Our results demonstrate that gefitinib reduces PC biosynthesis via inhibition of cellular choline uptake by A549 and rat ATII
cells, which is mainly mediated by CTL1, resulting in abnormality of lung surfactant that can be one of mechanisms of the
interstitial lung disease associated with gefitinib. |
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Keywords: | alveolar type II choline gefitinib lung toxicity phosphatidylcholine |
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