Carnitine/xenobiotics transporters in the human mammary gland epithelia, MCF12A
| Autor: | Ikumi Tamai, Haibo Xu, Shinya Ito, Patricia A. Harper, Lillian Chan, Bruce Kwok, Wen Gao, Ariko Yamauchi, Shinichiro Takahashi, Akira Tsuji, Jun-ichi Nezu, Upinder Dhillon, Bernice Wang, Ratheishan Rajesan, John W. Semple |
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| Rok vydání: | 2005 |
| Předmět: |
Organic Cation Transport Proteins
Physiology Metabolic Clearance Rate Mammary gland Xenobiotics chemistry.chemical_compound Physiology (medical) Metabolic clearance rate Carnitine medicine Humans Tissue Distribution Tissue distribution Mammary Glands Human Solute Carrier Family 22 Member 5 Barrier function Cells Cultured Organic cation transport proteins biology Symporters Transporter medicine.anatomical_structure Biochemistry chemistry biology.protein Female Xenobiotic medicine.drug |
| Zdroj: | American journal of physiology. Regulatory, integrative and comparative physiology. 290(3) |
| ISSN: | 0363-6119 |
| Popis: | The barrier function of the human mammary gland collapses if challenged with cationic drugs, causing their accumulation in milk. However, underlying molecular mechanisms are not well understood. To gain insight into the mechanism, we characterized transport of organic cations in the MCF12A human mammary gland epithelial cells, using carnitine and tetraethylammonium (TEA) as representative nutrient and xenobiotics probes, respectively. Our results show that the mammary gland cells express mRNA and proteins of human (h) novel organic cation transporters (OCTN) 1 and hOCTN2 (a Na+-dependent carnitine carrier with Na+-independent xenobiotics transport function), which belong to the solute carrier superfamily (SLC) of transporters. Other SLC OCTs such as hOCT1 and extraneuronal monoamine transporter (EMT)/hOCT3 are also expressed at mRNA levels, but hOCT2 was undetectable. We further showed mRNA expression of ATB0+ (an amino acid transporter with a Na+/Cl−-dependent carnitine transport activity), and Fly-like putative transporter 2/OCT6 (a splice variant of carnitine transporter 2: a testis-specific Na+-dependent carnitine transporter). TEA uptake was pH dependent. Carnitine uptake was dependent on Na+, and partly on Cl−, compatible with hOCTN2 and ATB0+ function. Modeling analyses predicted multiplicity of the uptake mechanisms with the high-affinity systems characterized by Km of 5.1 μM for carnitine and 1.6 mM for TEA, apparently similar to the reported hOCTN2 parameter for carnitine, and that of EMT/hOCT3 for TEA. Verapamil, cimetidine, carbamazepine, quinidine, and desipramine inhibited the carnitine uptake but required supratherapeutic concentrations, suggesting robustness of the carnitine uptake systems against xenobiotic challenge. Our findings suggest functional roles of a network of multiple SLC organic cation/nutrient transporters in human mammary gland drug transfer. |
| Databáze: | OpenAIRE |
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