HOMOZYGOUS DISRUPTION OF THE MURINE MDR2 P-GLYCOPROTEIN GENE LEADS TOA COMPLETE ABSENCE OF PHOSPHOLIPID FROM BILE AND TO LIVER-DISEASE

Two types of P-glycoprotein have been found in mammals: the drug-trans porting P-glycoproteins and a second type, unable to transport hydroph obic anticancer drugs. The latter is encoded by the human MDR3 (also c alled MDR2) and the mouse mdr2 genes, and its tissue distribution (bil e canalicular membrane of hepatocytes, B cells, heart, and muscle) sug gests a specialized metabolic function. We have generated mice homozyg ous for a disruption of the mdr2 gene. These mice develop a liver dise ase that appears to be caused by the complete inability of the liver t o secrete phospholipid into the bile. Mice heterozygous for the disrup ted allele had no detectable liver pathology, but half the level of ph ospholipid in bile. We conclude that the mdr2 P-glycoprotein has an es sential role in the secretion of phosphatidylcholine into bile and hyp othesize that it may be a phospholipid transport protein or phospholip id flippase.