Bromocriptine modulates P-glycoprotein function.
The multidrug resistance (MDR)-associated P-glycoprotein (P-gp) is a membrane transporter which carries, at the expense of MgATP hydrolysis, many amphiphilic molecules, such as the MDR-related cytotoxic drugs vincristine and vinblastine, and the MDR-reversing agents verapamil and progesterone. We have tested the effects on P-gp function of bromocriptine (BCT), an ergot alkaloid known as a D2 dopaminergic receptor agonist. BCT (at 4 microM) partially reverses the P-gp-mediated vincristine resistance of the Chinese hamster lung fibroblasts DC-3F/ADX, a MDR cell line. P-gp containing membrane vesicles prepared from the DC-3F/ADX cells exhibit, in the absence of any added drug, a basal MgATPase activity due to P-gp. BCT inhibits this basal ATPase activity, with a half-inhibiting concentration of 0.30 +/- 0.15 microM. BCT also inhibits the verapamil-induced P-gp ATPase stimulation competitively (Ki approximately 0.2 microM), and the progesterone-induced P-gp ATPase stimulation non-competitively (Ki approximately 0.07-0.10 microM). BCT also non-competitively inhibits the vinblastine-dependent P-gp ATPase activity within the same concentration range. Hydroxylated metabolites of BCT have different effects on P-gp ATPase, only the monohydroxylated being able to modulate both the basal and the drug-stimulated ATPase activities. In conclusion, these effects of BCT on P-gp function can be linked to a specific interaction with P-gp, probably involving inhibition of P-gp-mediated drug transport.
Orlowski
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S
Section de Biophysique des Protéines et des Membranes, DBCM, CEA, Centre d'Etudes de Saclay, Gif/Yvette, France. orlowski@dsvidf.cea.fr
Valente
D
D
Garrigos
M
M
Ezan
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D001971:Bromocriptine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors; D002461:Cell Line, Transformed; D006224:Cricetinae; D018491:Dopamine Agonists / Q000494:pharmacology; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D006900:Hydroxylation; D007700:Kinetics; D011374:Progesterone / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018491:Dopamine Agonists; D001971:Bromocriptine; D011374:Progesterone; D014750:Vincristine; D017301:Ca(2+) Mg(2+)-ATPase