MDR3 Under Development

MDR3 (multidrug resistance protein 3)

Aliases: P-glycoprotein 3, PGY3

Gene name: ATP-binding cassette, sub-family B (MDR/TAP), member 4 (ABCB4)

Summary

Bile formation is one of the most essential functions of the liver. On the canalicular membrane of hepatocytes, several ABC transporters are known to be involved in the biliary secretion of bile lipids, organic solutes, and xenobiotics. Among them, MDR3 is responsible for the secretion of phospholipids from hepatocytes into bile. It is almost exclusively expressed in the liver, with much lower mRNA expression levels in the adrenal gland, muscle, tonsil, spleen, placenta, testis, and ileum. ABCB4 mutations result in a broad spectrum of phenotypes ranging from progressive familial intrahepatic cholestasis type 3 (PFIC3) to MDR3-related cholestatic liver disorders of varying manifestation and severity in adults. Because MDR3 plays an essential role in the process of bile formation, inhibition of its function by drugs and/or their metabolites may be related to cholestasis and drug-induced liver injury (DILI). At present, while several drugs have been reported to inhibit BSEP function, little is known about the inhibition of MDR3 by cholestatic drugs. Compared to other drug transporters there are only few identified drug substrates and inhibitors of MDR3; thus, knowledge of its involvement in drug-drug interactions (DDI) is very limited. .

Localization

MDR3 is predominantly expressed in the apical (canalicular) membrane of hepatocytes and is necessary for the secretion of phospholipids into bile [1]. In MDR3-expressing HEK293 cells, MDR3 was mainly distributed into the nonraft membranes; likewise, in mouse canalicular membranes, Abcb4 was exclusively localized to the nonraft membranes [2]. Low levels of mRNA expression have also been reported in the adrenal gland, muscle, tonsil, spleen, placenta, testis, and ileum [3].

Function, physiology, and clinically significant polymorphisms

The MDR3 transporter, a ~140 kDa protein, has been predicted to be a floppase that translocates phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer. Translocation of PC makes the biliary phospholipids available for extraction into the canalicular lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts [4]. However, the molecular mechanism of MDR3-mediated phospholipid efflux is poorly understood. Several drugs may lead to cholestasis by functionally impairing the activity of canalicular transporters. It is thought that inhibition of MDR3 can contribute mechanistically to the manifestation of cholestasis and impact the hepatocellular/biliary toxicity of bile acids. To date, only few studies have addressed the role of lipid transporters in drug interactions [5].
MDR3 and MDR1 (P-gp) have a few common substrates including digoxin, paclitaxel and vinblastine [6], although a role for MDR3 in clinical drug transport has not been established.
A growing number of ABCB4 disease-causing variations is being revealed [7, 8]. The most severe of these diseases is progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare autosomal recessive liver disorder characterized by early onset of persistent cholestasis that progresses to cirrhosis and liver failure which may be lethal in the absence of liver transplantation. Less severe are the low phospholipid-associated cholelithiasis (LPAC) syndrome and intrahepatic cholestasis of pregnancy (ICP), which occur in the young adult [9].

Clinical significance

PFIC3 is hallmarked by high serum gamma glutamyl transpeptidase (GGT) and early onset of persistent cholestasis that progresses to cirrhosis and liver failure before adulthood. The biliary phospholipid levels in PFIC3 patients are greatly decreased despite the presence of bile acids. This cholestasis may be caused by the toxicity of detergent bile salts that are not associated with phospholipids, resulting in injury of biliary epithelium and bile canaliculi. In many cases of PFIC3, liver transplantation is the only therapy [10].
LPAC syndrome is the main hepatic condition associated with ABCB4/MDR3 in adults. It is mainly characterized by intrahepatic lithiasis and, in severe forms, by bile duct dilatations and rarely, secondary cholangitis. (reviewed in [11]). ICP, also called obstetric cholestasis, is a liver condition of pregnancy, characterized by pruritus and the biochemical finding of elevated serum bile acids, often in the presence of other signs of liver dysfunction [12].

Regulatory requirements

MDR3 is not currently recommended for investigation by regulatory guidelines.

Table: Summary information for MDR3

References

1.    Cheng, X., D. Buckley, and C.D. Klaassen, Regulation of hepatic bile acid transporters Ntcp and Bsep expression. Biochem Pharmacol, 2007. 74(11): p. 1665-76.
2.    Choudhuri, S., et al., Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab Dispos, 2003. 31(11): p. 1337-45.
3.    Kis, E., et al., BSEP inhibition - In vitro screens to assess cholestatic potential of drugs. Toxicol in Vitro, 2011.
4.    Kivisto, K.T. and M. Niemi, Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm Res, 2007. 24(2): p. 239-47.
5.    Dawson, S., et al., In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab Dispos, 2012. 40(1): p. 130-8.
6.    Smith, A.J., et al., MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem, 2000. 275(31): p. 23530-9.
7.    Ho, R.H., et al., Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics, 2010. 20(1): p. 45-57.
8.    Dixon, P.H., et al., Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut, 2009. 58(4): p. 537-44.
9.    Meier, Y., et al., Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology, 2006. 44(1): p. 62-74.
10.    Kosters, A. and S.J. Karpen, Bile acid transporters in health and disease. Xenobiotica, 2008. 38(7-8): p. 1043-71.
11.    Meier, Y., et al., Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump. World J Gastroenterol, 2008. 14(1): p. 38-45.
12.    Sahi, J., et al., Metabolism and transporter-mediated drug-drug interactions of the endothelin-A receptor antagonist CI-1034. Chem Biol Interact, 2006. 159(2): p. 156-68.