ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P‐glycoprotein
- 25 April 1994
- journal article
- Published by Wiley in FEBS Letters
- Vol. 343 (2) , 168-172
- https://doi.org/10.1016/0014-5793(94)80312-9
Abstract
The ATP‐dependent transport of the three 3H‐labeled, amphiphilic cations quinidine, N‐(n‐pentyl)‐quinidinium, and N‐(4',4'‐azo‐n‐pentyl) ‐21‐deoxyajmalinium was studied in rat canalicular plasma membrane vesicles. N‐Alkylation of quinidine with an n‐pentyl residue resulted in a permanently charged cationic substrate for ATP‐dependent transport which exhibited a 10‐fold higher transport rate relative to quinidine. The K m value was 0.4 μM for N‐(n‐pentyl)‐quinidinium and 5 μM for quinidine. The permanently cationic and photolabile derivative of ajmaline, N‐(4',4'‐azo‐n‐pentyl)‐21‐deoxyajmalinium, was also an efficient substrate and served to label canalicular membrane proteins with molecular masses of 143 kDa and 108 kDa. ATP‐dependent transport of the permanently charged amphiphilic cations was inhibited by the P‐glycoprotein inhibitors and substrates quinidine, verapamil, and daunorubicin. The data demonstrate that N‐alkylation of quinidine and ajmaline results in most efficient substrates for mdr1 P‐glycoprotein‐mediated ATP‐dependent transport.Keywords
This publication has 24 references indexed in Scilit:
- Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver diseasePublished by Elsevier ,1993
- Differential inhibition by cyclosporins of primary‐active ATP‐dependent transporters in the hepatocyte canalicular membraneFEBS Letters, 1993
- BIOCHEMISTRY OF MULTIDRUG RESISTANCE MEDIATED BY THE MULTIDRUG TRANSPORTERAnnual Review of Biochemistry, 1993
- The biology of the bile canaliculus, 1993Hepatology, 1993
- Canalicular Transport: Discovery of ATP-Dependent MechanismsToxicology and Applied Pharmacology, 1993
- Sufficient levels of quinine in the serum circumvent the multidrug resistance of the human leukemic cell line K562/ADMCancer, 1991
- Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cationsJournal of Pharmacokinetics and Biopharmaceutics, 1990
- Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat.Journal of Clinical Investigation, 1988
- Hereditary Chronic Conjugated Hyperbilirubinemia in Mutant Rats Caused by Defective Hepatic Anion TransportHepatology, 1985
- Diazirines. II. Synthesis and properties of small functionalized diazirine molecules. Observations on the reaction of a diaziridine with the iodine-iodide ion systemThe Journal of Organic Chemistry, 1970