Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis
✍ Scribed by J Deleuze; E Jacquemin; C Dubuisson; D Cresteil; M Dumont; S Erlinger; O Bernard; M Hadchouel
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 349 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Disruption of the murine mdr2 (multidrug-resistance) disease, characterized by a portal inflammation and a gene, which encodes a phosphatidylcholine flippase, ductular proliferation, is probably the consequence of leads to a hepatic disorder because of loss of biliary a toxic effect of bile acids on the biliary epithelium in phospholipid secretion. Among the hereditary human the absence of biliary phospholipids. 13,22 Because hucholestasis, a subtype of progressive familial intraheman bile acids are more hydrophobic than those of ropatic cholestasis with high g-glutamyltranspeptidase dents, it is expected that the absence of MDR3 P-glyco-(GGT) serum activity shares histological, biochemical, protein (the human homolog of mdr2 P-glycoprotein) and genetic features with mice lacking mdr2 gene exwould result in severe liver disease manifest in childpression (mdr2 0/0 mice). No MDR3 (human mdr2 homohood.
log) messenger RNA (mRNA) was detected by Northern
Progressive familial intrahepatic cholestasis (PFIC), blotting in the liver of a patient suffering from this form of PFIC, and the biliary phospholipid level in a second which is a recessive condition of childhood that results patient was substantially decreased. Thus, the absence in death of liver failure before adolescence, may correof the MDR3 P-glycoprotein may be responsible for this spond to such a liver disease. [23][24][25][26] Several studies have type of PFIC, which, as in the murine model, may be due recently provided support for the heterogeneity of this to a toxic effect of bile acids on the biliary epithelium clinical entity, suggesting the existence of different in absence of biliary phospholipids. (HEPATOLOGY 1996; causes: clinical, biochemical, and histological features 23:904-908.)
suggest at least three subcategories. [27][28][29][30] However, no associated genetic defect has been identified. It has The mouse mdr2 gene (standard gene symbol Pgybeen suggested that one subtype of PFIC may be attrib-3) and its human homolog MDR3 (also called MDR2, utable to a defect in primary bile acid secretion, 29 and it standard gene symbol PGY3) are members of the multihas been established that children affected by another drug gene family 1-7 that do not confer multidrug resissubtype have a defect in primary bile acid synthesis. 30 tance 8-11 but encode P-glycoproteins, which act as phos-In both of these subtypes, cholestasis is associated with phatidylcholine flippases. 12-17 These P-glycoproteins normal serum g-glutamyltranspeptidase (GGT) activare, in liver, exclusively found in the canalicular memity, and there is no ductular proliferation as assessed brane of hepatocytes. [18][19][20][21] Disruption of the mdr2 gene by liver histology. [29][30] By contrast, the pathological in mice has led to evidence for a physiological role of mechanism is unknown for the third subtype characthe mdr2 P-glycoprotein in biliary excretion. 13 In homoterized by high serum GGT activity and ductular prolifzygous mdr2 0/0 mice, phospholipids are absent from eration and inflammatory infiltrate in portal areas bile and the animals suffer from liver disease. 13,22 This with patency of intrahepatic and extrahepatic bile ducts. This pattern of nonsuppurative cholangitis is very similar to the hepatic injury observed in mdr2 0/ Abbreviations: PFIC, progressive familial intrahepatic cholestasis; GGT, g-0 mice. Therefore, it can be speculated that an abnorglutamyltranspeptidase; mRNA, messenger RNA; cDNA, complementary mality in the MDR3 P-glycoprotein gene expression DNA. may be the cause of this type of PFIC. To investigate From the 1 Unite ´INSERM U 347, le Kremlin Bice ˆtre, France; 2 Service d'he ´pathis possibility, we tested for the presence of messenger tologie, de ´partement de pe ´diatrie, Ho ˆpital de Bice ˆtre, le Kremlin Bice ˆtre, RNA (mRNA) encoding the MDR3 P-glycoprotein in the France; and