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1 Division of Tumor Biochemistry, German Cancer Research Center, Heidelberg, Germany
2 Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: m.rius{at}dkfz.de.
The multidrug resistance protein ABCC4 (MRP4), a member of the ATP-binding cassette superfamily, mediates ATP-dependent unidirectional efflux of organic anions out of cells. Previous studies showed that human ABCC4 is localized to the sinusoidal membrane of hepatocytes and mediates, among other substrates, the cotransport of reduced glutathione (GSH) with bile acids. In the present study, using inside out membrane vesicles, we demonstrated that human ABCC4 in the presence of physiological concentrations of GSH has a high affinity for the taurine and glycine conjugates of the common natural bile acids as well as the unconjugated bile acid cholate. Chenodeoxycholyltaurine and chenodeoxycholylglycine were the GSH cosubstrates with the highest affinities for ABCC4, with Km values of 3.6 and 5.9 µM, respectively. Ursodeoxycholyltaurine and ursodeoxycholylglycine were cotransported together with GSH by ABCC4 with Km values of 7.8 µM and 12.5 µM, respectively, but no transport of ursodeoxycholate and deoxycholate was observed. The simultaneous transport of labeled GSH and cholyltaurine or cholylglycine was demonstrated in double-label cotransport experiments with a bile acid to GSH ratio of about 1 to 22. Km values of the bile acids for ABCC4 were in a similar range as those reported for the canalicular bile salt export pump ABCB11 (BSEP). Under physiological conditions, the sinusoidal ABCC4 may compete with canalicular ABCB11 for bile acids and thereby play a key role in determining the hepatocyte concentration of bile acids. In cholestatic conditions, ABCC4 may become a key pathway for efflux of bile acids from hepatocytes into blood.
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