A paradigm for the Genetics of Adult Cholestatic Syndromes

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MDR3 (ABCB4) Defects: A Paradigm for the Genetics of Adult Cholestatic

Syndromes.

15 Feb 2007 09:00:17 -0800

Related Articles MDR3 (ABCB4) Defects: A Paradigm for the Genetics of

Adult Cholestatic Syndromes. Semin Liver Dis. 2007 Feb;27(1):77-98

Authors: Trauner M, Fickert P, Wagner M Because ATP-binding cassette

(ABC) transporters are important for normal bile secretion, hereditary

and acquired ABC transporter defects play a central role in the

pathogenesis of cholestasis. Defects of the phospholipid export pump

MDR3 ( ABCC4) result in impaired biliary excretion of

phosphatidylcholine and a variety of cholestatic syndromes ranging

from progressive familial intrahepatic cholestasis in neonates to

biliary cirrhosis in adults. Moreover, MDR3 mutations predispose to

cholestasis of pregnancy and drug-induced cholestasis. Because MDR2

(rodent orthologue of human MDR3) knockout mice develop sclerosing

cholangitis, it is attractive to speculate that MDR3 defects could

also play an important role in cholangiopathies in humans. Indeed,

MDR3 variants could play a role as modifier gene in primary biliary

cirrhosis and primary sclerosing cholangitis, but their exact role

needs further clarification. Impaired biliary phosphatidylcholine

excretion has also been reported in total parenteral nutrition-induced

cholestasis and bile duct injury following liver transplantation, but

a genetic basis for these findings remains to be explored. Several

drugs for the treatment of cholestatic liver diseases target MDR3

expression and function, further underscoring the clinical

significance of this transport system. PMID: 17295178 [PubMed - in

process]