Tissue Distribution and Induction of Human Multidrug Resistant Protein 3

Abstract

SUMMARY:The multidrug resistance protein (MRP) family consists of several members and, for some of these transporter proteins, distinct roles in multidrug resistance and normal tissue functions have been well established (MRP1 and MRP2) or are still under investigation (MRP3). MRP3 expression studies in human tissues have been largely restricted to the mRNA level. In this report we extended these studies and further explored MRP3 expression at the protein level. Western blot and immunohistochemistry with two MRP3-specific monoclonal antibodies, M 3 II-9 and M 3 II-21, showed MRP3 protein to be present in adrenal gland, and kidney and in tissues of the intestinal tract: colon, pancreas, gallbladder, and liver. In epithelia, MRP3 was found to be located at the basolateral sides of cell membranes. In normal liver, MRP3 was detected at lower levels than anticipated from the mRNA data and was found present mainly in the bile ducts. In livers from patients with various forms of cholestasis, MRP3 levels were frequently increased in the proliferative cholangiocytes, with sometimes additional staining of the basolateral membranes of the hepatocytes. This was especially evident in patients with type 3 progressive familial intrahepatic cholestasis. The present results support the view that MRP3 plays a role in the cholehepatic and enterohepatic circulation of bile and in protection within the biliary tree and tissues along the bile circulation route against toxic bile constituents. The possible functional roles for MRP3 in the adrenal gland and in the kidney remain as yet unknown. In a panel of 34 tumor samples of various histogenetic origins, distinct amounts of MRP3 were detected in a limited number of cases, including lung, ovarian, and pancreatic cancers. These findings may be of potential clinical relevance when considering the drug treatment regimens for these tumor types. (Lab Invest 2002, 82:193-201).

Differential Modulation of the Human Liver Conjugate Transporters MRP2 and MRP3 by Bile Acids and Organic Anions

“…In this case several compounds, normally extruded into the bile, are transported by MRP3 into the sinusoidal blood. MRP3 is also up-regulated under cholestatic conditions and agents (23)(24)(25). Thus the co-regulated function of MRP2 and MRP3 may have a major effect on the conjugate metabolism and bile acid secretion in the human liver.…”

The MRP family of drug efflux pumps

“…However, the observation that mrp3 À/À mice are healthy (M Belinsky and G Kruh, unpublished data) suggests that MRP3 is not likely to play an important role in this essential process. In addition to gut and liver, MRP3 is expressed in a variety of other tissues, including pancreas, kidney, adrenal and gallbladder Kiuchi et al, 1998;Uchiumi et al, 1998;Scheffer et al, 2002b). The functions of the pump in these and other tissues may be revealed by investigations of mrp3-deficient mice.…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…However, it is generally accepted that the absorptive transporters ASBT, MRP3, MCT1, OATP2B1 and OSTa/b have moderate to high intestinal expression levels. [12,[14][15][16]18,20,21,29,32,33,36,39,40] The three known intestinal exsorptive transporters for organic anions (BCRP, MRP2 and OSTa/b) all have relatively high expression levels -especially BCRP has a high intestinal expression compared with other tissues. [14,16,18,20,21,23,39] A high transporter expression level is likely indicative of an important role in the absorption or elimination of endogenous and exogenous substances.…”

“…Jejunum > colon [14] Colon > ileum, not in jejunum [24] MRP1 ABCC1 Ab Jejunum = ileum = colon [27] Jejunum, ileum > duodenum [28] Jejunum = colon [14] Duodenum [19] Jejunum [20] Small intestine [21,29] Colon [29,30] Small intestine and colon [31] Too low expression in jejunum, ileum and colon for protein determination [29] MRP2 ABCC2 Ex Jejunum > ileum > > colon [27] Duodenum > ileum > > colon [32] Duodenum = ileum > colon [16] Jejunum, ileum > duodenum [28] Duodenum > > colon [33] Jejunum > colon [18] Duodenum [19] Jejunum [16,20] Small intestine [21] Jejunum > ileum = colon [27] MRP3 ABCC3 Ab Colon > Ileum = duodenum [16] Jejunum, ileum > duodenum [28] Colon > jejunum [18] Duodenum [19] Jejunum [16,20] Small intestine [21,32] Colon [28,32] Small intestine and colon [29] MRP4 ABCC4 N.R. Jejunum, ileum > duodenum [28] Jejunum = colon [14] Jejunum [20] Small intestine [21,32] Colon [28,32] N.R.…”