Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells

• Published in: Biochimica et biophysica acta 2009-05, Vol.1788 (5), p.911-917
• Main Authors: Seki, Satoru, Kobayashi, Masaki, Itagaki, Shirou, Hirano, Takeshi, Iseki, Ken
• Format: Article
• Language: English
• Subjects: AIPT; Alveolar epithelial type II; Amiodarone; Amiodarone - pharmacokinetics; Amiodarone - toxicity; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - toxicity; Base Sequence; Biological Transport, Active - drug effects; Cell Line; DNA Primers - genetics; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Humans; Kinetics; OATP2B1; Organic Anion Transporters - antagonists & inhibitors; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Pulmonary Alveoli - cytology; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/j.bbamem.2009.03.003

The accumulation mechanisms of amiodarone (AMD) involving transporters in lung alveolar epithelial type II cells were studied. The uptake of AMD was examined using human alveolar epithelial-derived cell line A549 as a model. AMD was transported by the carrier-mediated system, and the apparent K m and V max values were 66.8 ± 30.3 μM and 49.7 ± 9.7 nmol/mg protein/5 min, respectively. The uptake of AMD by A549 cells was Na +-independent and was inhibited by substrates of human organic anion transporting polypeptide (OATP). The inhibition profiles were similar to the inhibitory effects of several compounds on OATP2B1-mediated E-3-S transport, and RT-PCR analysis showed mRNA expression of OATP2B1 and 1B3 in A549 cells. SiRNAs targeted to the OATP2B1 gene decreased the OATP2B1 mRNA expression level in A549 cells up to about 50% and reduced the uptake of AMD up to about 40%. These results indicate that AMD uptake mediated by carriers, including OATP2B1, might lead to accumulation of AMD in the lung and AMD-induced pulmonary toxicity (AIPT).