Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis.
Disruption of the murine mdr2 (multidrug-resistance) gene, which encodes a phosphatidylcholine flippase, leads to a hepatic disorder because of loss of biliary phospholipid secretion. Among the hereditary human cholestasis, a subtype of progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase (GGT) serum activity shares histological, biochemical, and genetic features with mice lacking mdr2 gene expression (mdr2 -/- mice). No MDR3 (human mdr2 homolog) messenger RNA (mRNA) was detected by Northern blotting in the liver of a patient suffering from this form of PFIC, and the biliary phospholipid level in a second patient was substantially decreased. Thus, the absence of the MDR3 P-glycoprotein may be responsible for this type of PFIC, which, as in the murine model, may be due to a toxic effect of bile acids on the biliary epithelium in absence of biliary phospholipids.
Deleuze
J F
JF
Unité INSERM U 347, le Kremlin Bicêtre, France.
Jacquemin
E
E
Dubuisson
C
C
Cresteil
D
D
Dumont
M
M
Erlinger
S
S
Bernard
O
O
Hadchouel
M
M
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis*; D005723:gamma-Glutamyltransferase / Q000097:blood
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; C095122:multidrug resistance protein 3; D005723:gamma-Glutamyltransferase