Decreased biosynthesis of lung surfactant constituent phosphatidylcholine due to inhibition of choline transporter by gefitinib in lung alveolar cells.
OBJECTIVE
We investigated whether gefitinib, an anticancer agent, inhibits phosphatidylcholine (PC) biosynthesis and choline uptake by alveolar epithelial type II cells.


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 microM, 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 microM and 10.5 microM, 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.
Ishiguro
Naoki
N
Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamasaki, Noda, Chiba, 278-8510, Japan.
Oyabu
Masanobu
M
Sato
Toshihiro
T
Maeda
Tomoji
T
Minami
Hironobu
H
Tamai
Ikumi
I
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000099254:Organic Cation Transporter 3
D015703:Antigens, CD; D002794:Choline; D000077156:Gefitinib; D027701:Organic Cation Transport Proteins; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D011799:Quinazolines; D000099254:Organic Cation Transporter 3; C510732:SLC44A1 protein, human