pgp - publications

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1. Acta Pharmacol Sin. 2012 Apr 30. doi: 10.1038/aps.2012.25. [Epub ahead of print]

Biphasic regulation of P-glycoprotein function and expression by NO donors in
Caco-2 cells.

Duan R, Hu N, Liu HY, Li J, Guo HF, Liu C, Liu L, Liu XD.

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical
University, Nanjing 210009, China.

Aim:To investigate the effects of nitric oxide (NO) donors on the function and
expression of P-glycoprotein (P-gp) in Caco-2 cells.Methods:Caco-2 cells were
exposed to NO donors for designated times. P-gp function and expression were
assessed using Rhodamine123 uptake assay and Western blotting, respectively.
Intracellular reactive oxygen species (iROS) and intracellular reactive nitrogen
species (iRNS) levels were measured using ROS and RNS assay kits,
respectively.Results:Exposure of Caco-2 cells to 0.1 or 2 mmol/L of sodium
nitroprusside (SNP) affected the function and expression of P-gp in
concentration- and time-dependent manners. A short-term (4 h) exposure reduced
P-gp function and expression accompanied with significantly increased levels of
iROS and iRNS. In contrast, a long-term (24 h) exposure stimulated the P-gp
function and expression. The stimulatory effects of 2 mmol/L SNP was less
profound as compared to those caused by 0.1 mmol/L SNP. The other NO donors SIN-1
and SNAP showed similar effects. Neither the NO scavenger PTIO (2 mmol/L) nor
soluble guanylate cyclase inhibitor ODQ (50 μmol/L) reversed the SNP-induced
alteration of P-gp function. On the other hand, free radical scavengers
ascorbate, glutathione and uric acid (2 mmol/L for each), PKC inhibitor
chelerythrine (5 μmol/L), PI3K/Akt inhibitor wortmannin (1 μmol/L) and p38 MAPK
inhibitor SB203580 (10 μmol/L) reversed the upregulation of P-gp function by the
long-term exposure to SNP, but these agents had no effect on the impaired P-gp
function following the short-term exposure to SNP.Conclusion:NO donors
time-dependently regulate P-gp function and expression in Caco-2 cells:
short-term exposure impairs P-gp function and expression, whereas long-term
exposure stimulates P-gp function and expression. The regulation occurs via a
NO-independent mechanism.

PMID: 22543702 [PubMed - as supplied by publisher]