40 DEFECT OF MULTIDRUG RESISTANCE 3 (MDR3) 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 due to loss of biliary phospholipid secretion. Among the hereditary human cholestasis, a subtype of progressive familial intrahepatic cholestasis (PFIC) with high gamma-glutamyltranspeptidase (GGT) serum activity shares histological, biochemical and genetic features with mice lacking mdr2 gene expression (mdr2 -/- mice). Two patients presenting with this subtype of chronic cholestasis begining during the first year of life were studied. Liver histology showed the presence of ductular proliferation with patent extra and intahepatic bile ducts. The two patients underwent liver transplantation. In one patient no MDR3 (human mdr2 homologue) mRNA was detected in the liver by Northern blotting but no bile sample from this patient was available. However, we have studied the bile of the second patient for whom liver RNA isolation was not possible. The phospholipid concentration was substantially decreased: 2.2 mM which represented only 7.2% of total biliary lipids (in control cholestatic children, the mean phospholipid concentration was 36.6 mM representing 19.8% of total biliary lipids). 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.