Analysis of the mechanism for the development of cholestasis induced by the altered function of efflux transporters

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Multidrug resistance associate protein 2 (MRP2/ABCC2), which is expressed on the bile canalicular membrane, is involved in the formation of bile acid-independent bile flow, and its hereditary defect results in the development of Dubin-Johnson syndrome in humans. Cholestasis is also induced by many acquired factors. As the mechanism for the acquired cholestasis, it is possible for us to assume that MRP2/ABCC2 is internalized by certain kinds of pathogenic stimuli. In the present study, we have demonstrated that MRP2/ABCC2 is internalized under pathological conditions, and proposed that such an internalization of efflux transporter may be related to the pathogenesis of cholestasis. We have also analyzed the localization and function of the SNPs forms of MRP2 molecules, and suggested that some kinds of mutation, which are not directly associated with the reduced function of MRP2/ABCC2 molecules per se, may be associated with the altered intracellular localization, and therefore, with the reduced in vivo function compared with the wild type transporter. In addition, it has been demonstrated that MRP3/ABCC3 is induced on the basolateral membrane under pathological conditions, in order to compensate for the reduced function of MRP2/ABCC2. Since the extent of the stage of cholestasisd may be affected by the function of MRP3/ABCC3, we have examined the function of human MRP3/ABCC3. It was demonstrated that MRP3/ABCC3 accepts MRP2/ABCC2 substrates, along with the monovalent bile salts which are the selective substrates for the bile salt export pump (BSEP/ABCB11). Together with our findings with the perfused liver, we could identify MRP3/ABCC3 as the membrane protein which may be involved in the rescue of hepatocytes under pathological conditions. It was also suggested that the extent of MRP3/ABCC3 induction may affect the severitv of the cholestasis.