Abstract:
:Our aim has been to elucidate the possible mechanism of CJX1, an amlodipine derivative, in the modulation of P-gp function by determining its effect on P-gp ATPase activity. Basal P-gp ATPase activity was increased by CJX1 with half-maximal activity concentration (Km) of 8.6+/-1.4 microM. Kinetic analysis indicated a non-competitive inhibition of Verapamil (Ver)-stimulated P-gp ATPase activity by CJX1 and competitive inhibition of CJX1-stimulated P-gp ATPase activity by tetrandrine (Tet). The effect of CsA on CJX1-stimulated and Ver-stimulated P-gp ATPase activity was non-competitive and competitive inhibition, respectively. These findings implying that CJX1 and Tet can bind P-gp either on overlapping sites or distinct but interacting sites, while CJX1 and Ver as well as CsA can bind P-gp on separated sites in K562/DOX cells. Furthermore, the combined effect of CJX1 and Ver has been evaluated isobolographically in numerous fixed-ratio combinations of 1:1, 1:2, 1:4, 1:8, 1:10 in K562/DOX cells. The results show that mixtures of both drugs at these fixed-ratios exerted synergistic interactions, indicating that when the two reverses that bind P-gp on separated sites are combined, each can contribute to the overall interaction with P-gp, leading to the greater effect than that by either agent alone.
journal_name
Cell Biol Intjournal_title
Cell biology internationalauthors
Ji BS,He Ldoi
10.1016/j.cellbi.2009.06.023subject
Has Abstractpub_date
2009-10-01 00:00:00pages
1073-8issue
10eissn
1065-6995issn
1095-8355pii
S1065-6995(09)00166-8journal_volume
33pub_type
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