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Xenobiotica
the fate of foreign compounds in biological systems
Volume 46, 2016 - Issue 2
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Xenobiotic transporters

Interaction of six protoberberine alkaloids with human organic cation transporters 1, 2 and 3

, , , , , , , & show all
Pages 175-183 | Received 08 Apr 2015, Accepted 26 May 2015, Published online: 02 Jul 2015
 

Abstract

1. Organic cation transporters (OCTs) play an important role in drug safety and efficacy. Protoberberine alkaloids are ubiquitous organic cations or weak bases with remarkable biological actives. This study was to elucidate the potential interaction of alkaloids (coptisine, jatrorrhizine, epiberberine, berberrubine, palmatine and corydaline) with OCTs using Madin–Darby canine kidney (MDCK) cells stably expressing human OCT1, OCT2 and OCT3.

2. All the tested alkaloids significantly inhibited the uptake of MPP+, a model OCT substrate, in MDCK-hOCTs cells with the IC50 of 0.931–9.65 μM. Additionally, coptisine, jatrorrhizine and epiberberine were substrates of all the hOCTs with the Km of 0.273–5.80 μM, whereas berberrubine was a substrate for hOCT1 and hOCT2, but not for hOCT3, the Km values were 1.27 and 1.66 μM, respectively. The transport capacity of coptisine in MDCK cells expressing the variants of hOCT1-P341L or hOCT2-A270S was significantly higher than that in wild-type (WT) cells with the Clint (Vmax/Km) of 379 ± 7.4 and 433 ± 5.7 μl/mg protein/min, respectively.

3. The above data indicate that the tested alkaloids are potent inhibitors, and coptisine, jatrorrhizine, epiberberine and berberrubine are substrates of hOCT1, hOCT2 and/or hOCT3 with high affinity. In addition, the variants (OCT1-P341L and OCT2-A270S) possess higher transport capacity to coptisine than WT hOCTs.

Declaration of interest

This work was supported by the Zhejiang Nature Science Foundation of China (LY14H310007), by the National Natural Science Foundation of China (81373474) and National Major Projects for Science and Technology Development of Ministry Science and Technology of China (2012ZX09506001-004).

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