THE SISTER OF P-GLYCOPROTEIN REPRESENTS THE CANALICULAR BILE-SALT EXPORT PUMP OF MAMMALIAN LIVER

Canalicular secretion of bile salts is a vital function of the vertebr ate liver, yet the molecular identity of the involved ATP-dependent ca rrier protein has not been elucidated. We cloned the full-length cDNA of the sister of P-glycoprotein (spgp; M-r similar to 160,000) of rat liver and demonstrated that it functions as an ATP-dependent bile salt transporter in cRNA injected Xenopus laevis oocytes and in vesicles i solated from transfected Sf9 cells. The latter demonstrated a 5-fold s timulation of ATP dependent taurocholate transport as compared with co ntrols. This spgp-mediated taurocholate transport was stimulated solel y by ATP, was inhibited by vanadate, and exhibited saturability with i ncreasing concentrations of taurocholate (K-m = 5 mu M). Furthermore, spgp-mediated transport rates of various bile salts followed the same order of magnitude as ATP-dependent transport in canalicular rat liver plasma membrane vesicles, i.e. taurochenodeoxycholate > tauroursodeox ycholate = taurocholate > glycocholate = cholate. Tissue distribution assessed by Northern blotting revealed predominant, if not exclusive, expression of spgp in the liver, where it was further localized to the canalicular microvilli and to subcanalicular vesicles of the hepatocy tes by in situ immunofluorescence and immunogold labeling studies. The se results indicate that the sister of P-glycoprotein is the major can alicular bile salt export pump of mammalian liver.