Regulation of biotransformation systems and ABC transporters by benznidazole in HepG2 cells: involvement of pregnane X-receptor
Background Benznidazole (BZL) is the only antichagasic drug available in most endemic countries. Its effect on the expression and activity of drug-metabolizing and transporter proteins has not been studied yet. Methodology/Principal Findings Expression and activity of P-glycoprotein (P-gp), Multidru...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2012
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| In: |
PLoS neglected tropical diseases
Year: 2012, Volume: 6, Issue: 12 |
| ISSN: | 1935-2735 |
| DOI: | 10.1371/journal.pntd.0001951 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1371/journal.pntd.0001951 Verlag, kostenfrei, Volltext: http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001951 
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| Author Notes: | Juan P. Rigalli, Virginia G. Perdomo, Marcelo G. Luquita, Silvina S.M. Villanueva, Agostina Arias, Dirk Theile, Johanna Weiss, Aldo D. Mottino, María L. Ruiz, Viviana A. Catania |
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| 245 | 1 | 0 | |a Regulation of biotransformation systems and ABC transporters by benznidazole in HepG2 cells |b involvement of pregnane X-receptor |c Juan P. Rigalli, Virginia G. Perdomo, Marcelo G. Luquita, Silvina S.M. Villanueva, Agostina Arias, Dirk Theile, Johanna Weiss, Aldo D. Mottino, María L. Ruiz, Viviana A. Catania |
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| 520 | |a Background Benznidazole (BZL) is the only antichagasic drug available in most endemic countries. Its effect on the expression and activity of drug-metabolizing and transporter proteins has not been studied yet. Methodology/Principal Findings Expression and activity of P-glycoprotein (P-gp), Multidrug resistance-associated protein 2 (MRP2), Cytochrome P450 3A4 (CYP3A4), and Glutathione S-transferase (GST) were evaluated in HepG2 cells after treatment with BZL. Expression was estimated by immunoblotting and real time PCR. P-gp and MRP2 activities were estimated using model substrates rhodamine 123 and dinitrophenyl-S-glutathione (DNP-SG), respectively. CYP3A4 and GST activities were evaluated through their abilities to convert proluciferin into luciferin and 1-chloro-2,4-dinitrobenzene into DNP-SG, respectively. BZL (200 µM) increased the expression (protein and mRNA) of P-gp, MRP2, CYP3A4, and GSTπ class. A concomitant enhancement of activity was observed for all these proteins, except for CYP3A4, which exhibited a decreased activity. To elucidate if pregnane X receptor (PXR) mediates BZL response, its expression was knocked down with a specific siRNA. In this condition, the effect of BZL on P-gp, MRP2, CYP3A4, and GSTπ protein up-regulation was completely abolished. Consistent with this, BZL was able to activate PXR, as detected by reporter gene assay. Additional studies, using transporter inhibitors and P-gp-knock down cells, demonstrated that P-gp is involved in BZL extrusion. Pre-treatment of HepG2 cells with BZL increased its own efflux, as a consequence of P-gp up-regulation. Conclusions/Significance Modifications in the activity of biotransformation and transport systems by BZL may alter the pharmacokinetics and efficiency of drugs that are substrates of these systems, including BZL itself. | ||
| 650 | 4 | |a Cell membranes | |
| 650 | 4 | |a Drug metabolism | |
| 650 | 4 | |a High performance liquid chromatography | |
| 650 | 4 | |a Messenger RNA | |
| 650 | 4 | |a Protein expression | |
| 650 | 4 | |a Small interfering RNAs | |
| 650 | 4 | |a Trypanosoma cruzi | |
| 650 | 4 | |a Xenobiotic metabolism | |
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