The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes

doi:10.1016/S0065-2571(96)00013-1

Advances in Enzyme Regulation

Volume 37, 1997, Pages 321-333

https://doi.org/10.1016/S0065-2571(96)00013-1 Get rights and content

Abstract

The conjugate export pump in the hepatocyte canalicular membrane is, together with the ATP-dependent bile salt export pump, one of the two major pumps determining canalicular anion secretion and bile flow. The so-called bile salt-independent bile flow is largely driven by the cmrp/cmoat geneencoded conjugate export pump, as indicated by the markedly reduced bile flow in the $GY TR^{−}$ (11, 13–16) and the EHBR mutant rats (18–20). The importance of conjugation with glutathione (52, 53), glucuronate (11, 21), and sulfate (11, 16) for transfer of endogenous and xenobiotic substances from blood into bile has long been known. The molecular identification (7, 26, 54) and cloning (9, 10, 30) of the ATP-dependent export pump for these conjugates in the canalicular membrane was, at least in part, a consequence of the elucidation of the substrate specificity of the multidrug resistance protein (MRP) which is very similar to that of its canalicular isoform (3–6, 49). The broad substrate specificity of the conjugate export pump enables the terminal excretion of a multitude of conjugates and amphiphilic anions which are formed by a large number of relatively specific monooxygenases and transferases in phase I and phase II metabolism of endogenous and xenobiotic substances in the hepatocyte. The predominant expression of the conjugate export pump encoded by the cmrp/cmoat gene in the canalicular membrane does not exclude overexpression of this transporter in other cells and tissues when exposed to drugs and toxins that can be excreted by this pump. The apical conjugate export pump (8–10) may thus confer multidrug resistance to tumor cells in a similar manner as MRP1 (55). The observation that mRNA encoding rat cMrp/cMoat (10, 12) and its rabbit homolog (35) is not only detected in hepatocytes but also in small intestine and the kidneys suggests that the cmrp/cmoat gene-encoded conjugate export pump may function in the apical membrane domain of various epithelial cells.

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The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes

Abstract

Eur. J. Cancer

J. Biol. Chem.

J. Biol. Chem.

Hepatology

J. Biol. Chew.

J. Biol. Chem.

Hepatology

Gastroenterology

Comput. Methods Programs Biomed.

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Gene

J. Biol Chem.

Advan. Enzyme Regul.

Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line

Science

ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein

Cancer Res.

Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport

Transport of glutathione, glucuronate and sulfate conjugates by the MRP gene-encoded conjugate export pump

Cancer Res.

Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes

J. Cell Biol.

The canalicular conjugate export pump encoded by the cmrp/cmoat gene

Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene

Science

Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport

Biochim. Biophys. Acta

Molecular cloning of canalicular multispecific organic anion transporter defective in Eisai hyperbilirubinemic rats

Am. J. Physiol.

Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport

Hepatohgy

Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion

Hepatology