Pregnane X Receptor modulation by Mitragyna speciosa and its constituents

Traditionally, the leaves of Mitragyna speciosa which are consumed mainly by oral route are used in treating the withdrawal symptoms associated with opiate addiction and sometimes as an opioid substitute due to their euphoric effects in the brain. Pregnane X Receptor (PXR), a type of nuclear receptor, has been shown to transcriptionally regulate the expression of drug metabolizing enzymes and drug transporters. This study was carried out to evaluate the effects of Mitragyna speciosa methanolic extract, alkaloid rich fraction and its 6 alkaloids constituents on PXR activation. In addition, the changes in the expression (mRNA) of PXR target genes (CYP3A4, 1A2, and P-gp) were also determined. Modulation of PXR activity is monitored in hPXR transfected HepG2 cell line through a reporter gene assay, and quantitative RT-PCR was used to study the changes in the mRNA expression. The total extract, alkaloid rich fraction, and all six constituents showed significant activation of PXR which was comparable to the effects of standard drug, rifampicin. The mRNA expression of P-gp and CYP1A2 was also increased by the extract, alkaloid rich fraction and 4 of the constituents, while the expression of CYP3A4 was increased by the alkaloid rich fraction and 3 of the constituents. These results suggests that chronic intake of Mitragyna speciosa may lead to potential drug interactions as a result of PXR activation and increased expression of target genes thereby affecting the pharmacokinetics and pharmacodynamics of the conventional drugs that are substrates of CYPs and P-gp.