REGULATION OF MDR2 P-GLYCOPROTEIN EXPRESSION BY BILE-SALTS

The phosphatidyl translocating activity of the mdr2 P-glycoprotein (Pg p) in the canalicular membrane of the mouse hepatocyte is a rate-contr olling step in the biliary secretion of phospholipid. Since bile salts also regulate the secretion of biliary lipids, we investigated the in fluence of the type of bile salt in the circulation on mdr2 Pgp expre ssion and activity. Male mice were fed a purified diet to which either 0.1 % (w/w) cholate or 0.5 % (w/w) ursodeoxycholate was added. This l ed to a near-complete replacement of the endogenous bile salt pool (ma inly tauromuricholate) by taurocholate or tauroursodeoxycholate respec tively. The phospholipid secretion capacity was then determined by inf usion of increasing amounts of tauroursodeoxycholate Cholate feeding r esulted in a 55 % increase in maximal phospholipid secretion compared with that in mice on the control diet. Northern blotting revealed that cholate feeding increased mdr2 Pgp mRNA levels by 42 %. Feeding with ursodeoxycholate did not influence the maximum rate of phospholipid ou tput or the mdr2 mRNA content. Female mice had a higher basal mdr2 Pgp mRNA level than male mice, and this was also correlated with a higher phospholipid secretion capacity. This could be explained by the 4-fol d higher basal cholate content in the bile of female compared with mal e mice. Our results suggest that the type of bile salts in the circula tion influences the expression of the mdr2 gene.