ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P‐glycoprotein

FEBS Letters

Müller, Michael¹  Hero, Ulrike¹  Mayer, Rosmarie¹  Keppler, Dietrich¹ 

[1] Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany

关键词: Quinidine;    Ajmaline;    Multidrug resistance;    Taurocholate;    P-glycoprotein;    Liver;    APD-ajmalinium;    N-(4';    4'-azo-n-pentyl)-21-deoxy-[21-3H]ajmalinium;    BSEC;    bile salt export carrier;    CMV;    canalicular membrane vesicles;    LTEC;    leukotriene export carrier;    MDEC;    multidrug export carrier;    MDR;    multidrug resistance;    pentyl quinidinium;    N-(n-pentyl)-quinidinium;    RP;    reversed phase;   

DOI  :  10.1016/0014-5793(94)80312-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown