Background/Aims: Bile flow consists of bile salt-dependent bile flow (BSDF), generated by canalicular secretion of bile salts, and bile salt-independent flow (BSIF), probably of combined canalicular and ductular origin. Bile salt transport proteins have been identified in cholangiocytes, suggesting a role in control of BSDF and/or in control of bile salt synthesis through cholehepatic shunting. Methods: We studied effects of bile duct proliferation under non-cholestatic conditions in multidrug resistance-2 P-glycoprotein (Abcb4)-deficient multidrug resistance gene-2 (Mdr2(-/-)) mice. BSDF and BSIF were determined in wild-type and Mdr2(-/-) mice during infusion of step-wise increasing dosages of tauroursodeoxycholate (TUDC). Cholate synthesis rate was determined by 2H4-cholate dilution. Results were related to expression of transport proteins in liver and intestine. Results: During TUDC infusion, BSDF was increased by ∼ 50% and BSIF by ∼ 100% in Mdr2(-/-) mice compared with controls. Cholate synthesis rate was unaffected in Mdr2(-/-) mice. Hepatic expression of the apical sodium-dependent bile salt transporter (Asbt), its truncated form (tAsbt) and the multidrug resistance-related protein 3 were upregulated in Mdr2(-/-) mice. Conclusions: Bile duct proliferation in Mdr2(-/-) mice enhances cholehepatic shunting of bile salts, which is associated with a disproportionally high bile flow but does not affect bile salt synthesis. © Blackwell Munksgaard 2005. Chemicals / CAS: carrier protein, 80700-39-6; chenodeoxycholic acid, 474-25-9; cholic acid, 32500-01-9, 361-09-1, 81-25-4; deoxycholic acid, 83-44-3; lithocholic acid, 434-13-9; multidrug resistance protein 2, 256503-65-8; multidrug resistance protein 3, 231947-64-1; muricholic acid, 39016-49-4; tauroursodeoxycholic acid, 14605-22-2; bile acid binding proteins; Bile Acids and Salts; Carrier Proteins; Cholates; Deuterium, 7782-39-0; Membrane Glycoproteins; Organic Anion Transporters, Sodium-Dependent; P-glycoprotein 2; P-Glycoproteins; Phospholipids; RNA, Messenger; sodium-bile acid cotransporter, 145420-23-1; Symporters