title: Decreased biosynthesis of lung surfactant constituent phosphatidylcholine due to inhibition of choline transporter by gefitinib in lung alveolar cells.
abstract: 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.
authors.affiliation: Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamasaki, Noda, Chiba, 278-8510, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oyabu
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sato
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: 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
chemical_list: 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