Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers.

Inchinkoto (ICKT), a herbal medicine, has been recognized in Japan and China as a "magic bullet" for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT.

Mutations identified in the human multidrug resistance P-glycoprotein 3 (ABCB4) gene in patients with primary hepatolithiasis.

Primary hepatolithiasis (HL), highly prevalent in the Far East, including Japan, is characterized clinically by chronic proliferative cholangitis with frequent recurrences. In HL patients, hepatic hyposecretion of phospholipid due to decreased multidrug resistance P-glycoprotein 3 (MDR3; now referred to as ABCB4) expression levels (Hepatology 2001;33:1194-1205) may contribute to the formation of aggressive ductular lesions through a decreased formation of mixed micelles. However, specified factors underlying the decreased expression levels of MDR3 have not been well defined.

Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver.

Inchin-ko-to (ICKT), an herbal medicine, and its ingredients exert potent choleretic effects by a "bile acid-independent" mechanism. The current study was designed to determine whether ICKT or its ingredients potentiate multidrug resistance-associated protein 2 (Mrp2; Abcc2)-mediated choleresis in vivo. Biliary secretion of Mrp2 substrates and the protein mass, subcellular localization, and messenger RNA (mRNA) level of Mrp2 were assessed in rat liver after infusion of genipin, an intestinal bacterial metabolite of geniposide, a major ingredient of ICKT.

Increased expression of gallbladder cholecystokinin: a receptor in prairie dogs fed a high-cholesterol diet and its dissociation with decreased contractility in response to cholecystokinin.

A series of our studies have shown that formation of cholesterol-supersaturated bile in patients with cholesterol gallstone disease is causatively related to decreased gallbladder contractility and mucin hypersecretion by the gallbladder. Supersaturated bile may modify the composition of gallbladder membranes so that the transduction of smooth muscle regulatory signals is impaired, and it may enhance the inflammation-induced mucin secretion by the gallbladder. To achieve a better understanding of the mechanism by which supersaturated bile impairs the contractility, we studied changes in the expression levels of gallbladder cholecystokinin (CCK-A) receptor messenger ribonucleic acid (mRNA) in prairie dogs fed a high-cholesterol diet.