Bile acid inhibition of P-glycoprotein-mediated transport in multidrug-resistant cells and rat liver canalicular membrane vesicles.
To study the effect of bile acids on P-glycoprotein-mediated drug transport, we performed experiments using multidrug resistant cells and rat canalicular membrane vesicles. Cellular accumulation and efflux of rhodamine 123 were measured in drug-resistant cells by means of computerized quantitative image analysis and fluorescence microscopy. ATP-dependent [3H]daunomycin transport was studied by means of rapid filtration in canalicular membrane vesicles prepared from normal rats. Doxorubicin-sensitive (PSI-2) and -resistant (PN1A) 3T3 cells and human-derived hepatocellular carcinoma doxorubicin-sensitive and -resistant cells were used. Taurochenodeoxycholate and glycochenodeoxycholate, taurolithocholate and ursodeoxycholate (50 to 200 mumol/L) inhibited rhodamine 123 and [3H]daunomycin transport in multidrug-resistant cells and canalicular membrane vesicles, respectively, whereas taurocholate, taurodeoxycholate and tauroursodeoxycholate did not. Primary and secondary unconjugated bile acids had no effect. These results reveal that taurolithocholate, taurochenodeoxycholate and glycochenodeoxycholate and ursodeoxycholate inhibit P-glycoprotein-mediated drug transport function in multidrug resistant cell lines and in canalicular membrane vesicles. These results suggest possible interaction between P-glycoprotein function and bile acids in cholestasis and after treatment of patients with ursodeoxycholic or chenodeoxycholic acid.
Mazzanti
R
R
Department of Physiology, Tufts University, Boston, Massachusetts.
Fantappié
O
O
Kamimoto
Y
Y
Gatmaitan
Z
Z
Gentilini
P
P
Arias
I M
IM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001648:Bile Canaliculi / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics; D003864:Depression, Chemical; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D012235:Rhodamines; D020112:Rhodamine 123; D004317:Doxorubicin; D003630:Daunorubicin