Original Article

Interaction of multidrug resistance reversal agents with P-glycoprotein ATPase activity on blood-brain barrier.

Authors: Ling HE, Guo-Qing LIU


AIM: To gain further insights into the mechanism of the ATP-dependent interaction
of P-glycoprotein (P-gp) with various multidrug resistance (MDR) reversal agents.
METHODS: Bovine brain capillary endothelial cells (BCEC) were isolated from
cerebral gray matter using modifications of the mechanical homogenization
technique. Plasma membranes were prepared from BCEC. The P- gp adenosine
triphosphatase (ATPase) activity of the isolated BCEC membranes was estimated by
measuring inorganic phosphate liberation.
RESULTS: The basal P-gp ATPase activity was increased by verapamil (Ver),
vincristine (VCR), doxorubicin (Dox), tetrandrine (Tet), dauricine (DRC),
berbamine (BBM), and daurisoline (DRS), with respective half-maximal activity
concentrations Km of about 17, 5.9, 41, 2.3, 11, 23, and 22 micromol/L. Berberine
(BBR) produced a relatively slight activation. dl-Tetrahydropalmatine (dl-THP)
and l-tetrahydropalmatine (l-THP ) does not alter the basal P-gp ATPase activity.
Cyclosporin A (CsA) inhibited both the basal and the drug-stimulated ATPase
activity of P-gp with high affinity. Kinetic analysis indicated a competitive
inhibition of Ver- or VCR-stimulated ATPase activity and a noncompetitive
inhibition of Dox- or Tet-activated ATPase activity by CsA. Moreover, Dox
inhibited Tet-activated P-gp ATPase activity in a noncompetitive manner.
CONCLUSION: Various MDR reversal agents could interact with P-gp and alter its
ATPase activity in different manners. This is the result of the b road molecular
recognition specificity of P-gp. CsA, Ver, and VCR could bin d P-gp either on
overlapping sites or distant but interacting sites, while CsA, Dox, and Tet could
independently bind P-gp on separated sites on blood-brain barrier.

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