期刊
MOLECULAR PHARMACOLOGY
卷 79, 期 3, 页码 596-607出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.110.069971
关键词
-
资金
- Instituto de Salud Carlos III
- Fondo de Investigaciones Sanitarias [CP05/0135, PI070517, PI080151]
- Junta de Castilla y Leon [GR75-2008]
- Ministerio de Ciencia e Innovacion
- Plan Nacional de Investigacion Cientifica
- Desarrollo e Innovacion Tecnologica [BFU2006-12577, SAF2009-08493, SAF2010-15517]
- Fundacion Investigacion Medica Mutua Madrilena [Conv-VI, 2009]
- Fundacion Marcelino Botin
- Ministerio de Ciencia e Innovacion [AP2006-02465]
- Ministerio de Ciencia e Innovacion, Spain
- European Regional Development Fund [BFU2007-30688-E/BFI]
Organic anion-transporting polypeptides (OATPs) are involved in the liver uptake of many endogenous and xenobiotic compounds, such as bile acids and drugs, respectively. Using Xenopus laevis oocytes and Chinese hamster ovary (CHO) cells expressing rat Oatp1a1, human OATP1B1, or OATP1B3, the sensitivity of these transporters to extracellular/intracellular pH (pHo/pHi) and changes in plasma membrane potential (Delta Psi) was investigated. In X. laevis oocytes, nonspecific plasma membrane permeability increased only at pHo below 4.5. Above this value, both using oocytes and CHO cells, extracellular acidification affected differently the specific transport of taurocholic acid (TCA) and estradiol 17 beta-D-glucuronide (E(2)17 beta G) by Oatp1a1 (stimulation), OATP1B1 (inhibition), and OATP1B3 (stimulation). Changes in substrate uptake in the presence of valinomycin (K+-ionophore), carbonyl cyanide 3-chlorophenylhydrazone and nigericin (protonophores), and amiloride (Na+/H+-inhibitor) and cation replacement in the medium were studied with fluorescent probes for measuring substrate uptake (cholylglycyl amidofluorescein) and changes in pHi (SNARF-4F) and Delta Psi [DilC(1)(5)]. The results suggest that activity of these three carriers is sodium/potassium-independent and affected differently by changes in pHo and Delta Psi: Oatp1a1 was confirmed to be an electroneutral anion exchanger, whereas the function of both OATP1B1 and OATP1B3 was markedly affected by the magnitude of Delta Psi. Moreover, electrophysiological measurements revealed the existence of a net anion influx associated to OATP1B1/OATP1B3-mediated transport of TCA, E(2)17 beta G, and estrone-3-sulfate. Furthermore, a leakage of Na+ through OATP1B1 and OATP1B3, which is not coupled to substrate transport, was found. In conclusion, these results suggest that OATP1B1 and OATP1B3 are electrogenic transporters whose activity may be strongly affected under circumstances of displacement of local pH.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据