Exploring the Carbamazepine Interaction with Human Pregnane X Receptor and Effect on ABCC2 Using in Vitro and in Silico Approach.

Autor: Grewal GK; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India.; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Singh KD; Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, 630 004, India., Kanojia N; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India.; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Rawat C; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India.; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Kukal S; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India.; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Jajodia A; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Singhal A; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Misra R; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India., Nagamani S; Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, 630 004, India., Muthusamy K; Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, 630 004, India., Kukreti R; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB) Campus, New Delhi, India. ritus@igib.res.in.; Genomics and Molecular Medicine Unit,, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110 007, India. ritus@igib.res.in.
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2017 Jul; Vol. 34 (7), pp. 1444-1458. Date of Electronic Publication: 2017 Apr 21.
DOI: 10.1007/s11095-017-2161-z
Abstrakt: Purpose: Over expression of ATP-binding cassette transporters is considered one of the major reasons for non-responsiveness to antiepileptic drugs. Carbamazepine (CBZ), one of first line antiepileptic drug is known to influence ABCC2 expression but its exact molecular mechanism is unknown.
Methods: We investigated the effect of CBZ on expression of ABCC2 and pregnane X receptor (PXR) in HepG2 cell line and compared with hyperforin (agonist of PXR) and ketoconazole (antagonist of PXR) through realtime PCR and western blot assay. Involvement of PXR was demonstrated through nuclear translocation and RNA interference and related effect of CBZ on ABCC2 through functional activity assay. Molecular docking and dynamic simulation approach was used to understand the interaction of CBZ with PXR.
Results: CBZ and hyperforin increased the PXR and ABCC2 expression whereas reversed when present it in combination with ketoconazole. Experiments confirmed CBZ induced ABCC2 expression is PXR dependent. Molecular dynamic (MD) simulation and in vitro experiment indicated possibility of CBZ to be PXR agonist and PXR residue Gln285 to be important for CBZ-PXR interaction.
Conclusions: CBZ alters the functional activity of ABCC2 through PXR, which in turn can interfere with therapy. Mutational analysis of residues revealed the importance of Gln285 in ligand interaction.
Databáze: MEDLINE
Externí odkaz: