Abstract
The effect of benznidazole (BZL) on the expression and activity of P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 2 (MRP2, ABCC2), the two major transporters of endogenous and exogenous compounds, was evaluated in differentiated THP-1 cells. BZL induced P-gp and MRP2 proteins in a concentration-dependent manner. The increase in mRNA levels of both transporters suggests transcriptional regulation. P-gp and MRP2 activities correlated with increased protein levels. BZL intracellular accumulation was significantly lower in BZL-pre-treated cells than in control cells. PSC833 (a P-gp inhibitor) increased the intracellular BZL concentration in both pre-treated and control cells, confirming P-gp participation in BZL efflux.
Highlights
Treatment of intracellular infections requires the use of chemotherapeutic agents capable of penetrating eukaryotic cells and reaching an optimal concentration to eliminate the causal agent (Tulkens 1990)
We have observed the induction of P-gp and multidrug resistance-associated protein 2 (MRP2)/Mrp2 by BZL in HepG2 cells (Rigalli et al 2012) and in the liver and intestine of BZL-treated rats (Perdomo et al 2013)
Effect of BZL treatment on its intracellular concentration - When THP-1 cells were pre-treated with BZL (200 μM, 48 h) or vehicle, and further incubated with BZL (100 μM, 2 h) for BZL transport studies, its intracellular accumulation was significantly lower in pretreated cells (-18%), indicating a rise in drug extrusion (Fig. 3)
Summary
Treatment of intracellular infections requires the use of chemotherapeutic agents capable of penetrating eukaryotic cells and reaching an optimal concentration to eliminate the causal agent (Tulkens 1990). Ate the effect of BZL pre-treatment on the expression and activity of P-gp and MRP2, the two major transporters of endogenous and exogenous compounds, in differentiated THP-1 cells, as model of human macrophages.
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