Organic cation transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity
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- 作者：Meijuan Tu ; Siyuan Sun ; Kai Wang ; Xueying Peng ; Ruihan Wang ; Liping Li ; Su Zeng ; Hui Zhou ; Huidi Jiang
- 关键词：PAs ; pyrrolizidine alkaloids ; MCT ; monocrotaline ; OCT1 ; organic cation transporter 1 ; MDCK ; Madin&ndash ; Darby canine kidney ; MPP+ ; 1-methyl-4-phenylpyridinium ; d-THP ; d-tetrahydropalmatine ; DHM ; dehydromonocrotaline ; CYP ; cytochrome P450 ; ASP+ ; 4-(4-(dime
- 刊名：Toxicology
- 出版年：2013
- 出版时间：15 September, 2013
- 年：2013
- 卷：311
- 期：3
- 页码：225-230
- 全文大小：1337 K
文摘
Monocrotaline (MCT) is a kind of toxic retronecine-type pyrrolizidine alkaloids (PAs) from plants of Crotalaria, which can be bio-activated by cytochrome P450 (CYP) enzymes in liver and then induce hepatotoxicity. Since CYPs are localized in the endoplasmic reticulum, the influx of MCT to the liver is the key step for its hepatotoxicity. The objective of the present study was to investigate the role of organic cation transporter 1 (OCT1), a transporter mainly expressed in liver, in the uptake of MCT and in hepatotoxicity induced by MCT. The results revealed that MCT markedly inhibited the uptake of 1-methyl-4-phenylpyridinium (MPP+), an OCT1 substrate, in Madin-Darby canine kidney (MDCK) cells stably expressing human OCT1 (MDCK-hOCT1) with the IC50 of 5.52 ¡À 0.56 ¦ÌM. The uptake of MCT was significantly higher in MDCK-hOCT1 cells than in MDCK-mock cells, and MCT uptake in MDCK-hOCT1 cells followed Michaelis-Menten kinetics with the Km and Vmax values of 25.0 ¡À 6.7 ¦ÌM and 266 ¡À 64 pmol/mg protein/min, respectively. Moreover, the OCT1 inhibitors, such as quinidine, d-tetrahydropalmatine (d-THP), obviously inhibited the uptake of MCT in MDCK-hOCT1 cells and isolated rat primary hepatocytes, and attenuated the viability reduction and LDH release of the primary cultured rat hepatocytes caused by MCT. In conclusion, OCT1 mediates the hepatic uptake of MCT and may play an important role in MCT induced-hepatotoxicity.