Multidrug resistance-associated proteins 3, 4, and 5

Abstract

We summarize in this paper the recently published results on multidrug resistance-associated proteins 3, 4, and 5 (MRPs 3-5). MRP3 can transport organic compounds conjugated to glutathione, sulfate, or glucuronate, such as estradiol-17beta-glucuronide, bilirubin-glucuronides, and etoposide-glucuronide, and also bile salts and methotrexate. Studies in knockout mice have shown that Mrp3 contributes to the transport of morphine-3-glucuronide and acetaminophen-glucuronide from the liver into blood. There is no evidence for a major role of MRP3 in bile salt metabolism, at least in mice. The function of MRP3 in other tissues, notably the gut and the adrenal cortex, remains to be defined. MRP4 and MRP5 have attracted attention by their ability to transport cyclic nucleotides and many nucleotide analogs. The initial reports that MRP4 and 5 can transport cGMP with microM affinity have not been confirmed in recent work and the physiological importance of cyclic nucleotide transport by MRP4 and 5 remains to be determined. Transfected cells containing high concentrations of MRP4 and 5 are moderately resistant to base, nucleoside, and nucleotide analogs. The affinity of both transporters for nucleotide analogs is low (K (m) around 1 mM) and there is no evidence that the transport of these compounds results in resistance in vivo. The physiological function of MRP4 and 5 remains to be found.

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

“…28 ABCC4/MRP4 and ABCC5/MRP5 were demonstrated to transport cyclic nucleotides and nucleotide analogs, even if controversial results were obtained regarding the strength of substrate affinity. 51 Moreover, both transporters were thought to serve as overflow pumps under conditions where cGMP synthesis was impaired. 52 Induction of ABCC4 and ABCC5 gene expression suggests an increase in cAMP and cGMP accumulation/efflux due to MRP6 deficiency in PXE.…”

Measurement of Transport Activities of Bile Acids in Human Multidrug Resistance-Associated Protein 3 Using Liquid Chromatography-Tandem Mass Spectrometry

“…1. [2,2,3,4,4, H6]-T-CA (T-CA-d6, isotopic purity >98.5%) was used as an internal standard (IS) for the determination of bile acids by LC-ESI-MS/MS. An Oasis HLB 96-well plate cartridge (Waters Co., Milford, MA) was washed successively with ethanol (0.5 mL) and water (1 mL) prior to use.…”

“…1,2 In contrast to MRP2 and BSEP, multidrug resistance-associated protein 3 (MRP3, ABCC3) localized at the basolateral membrane in hepatocytes excretes organic anions and bile acids from the hepatocytes to the sinusoid. 3,4 Human MRP3 (hMRP3) has been shown to transport not only monovalent bile acids, but also divalent bile acids. [4][5][6] Human MRP3 transports monovalent bile acids, such as glycocholic acid (G-CA) at high rates, even if at low affinity.…”

“…3,8,9 It is thought that hMRP3 may compensate for the impaired functions of MRP2 and BSEP, and that hMRP3 functions as an efflux transporter from hepatocytes to circulating blood to switch the excretion route for organic anions, including bile acids, from bile to urine under pathologic conditions. 3,8,9 The transport properties of bile acids mediated by hMRP3 have been investigated by examining the ATP-dependent transport of common bile acids, such as G-CA, taurocholic acid (T-CA) and T-LCA-3S in isolated bile canalicular membrane vesicles or in membrane vesicles obtained from hMRP3-expressing cells. [4][5][6] In those investigations, bile acids labeled with a radioactive isotope (RI) have been widely used as substrates for hMRP3 vesicles.…”

Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients

“…Etoposide-glucuronide is one of its substrates 10 and fibroblasts of mice overexpressing ABCC3 show a high resistance against etoposide. 11 In pancreatic carcinomas the expression of ABCC3 mRNA was upregulated and was correlated with tumor grading.…”