Probing PXR activation and modulation of CYP3A4 by Tinospora crispa and Tinospora sinensis.

Ethnopharmacological Relevance: The two Tinospora species, T. crispa and T. sinensis, native to Southeast Asia, are integral components of various traditional preparations with structure-function claims to treat various disorders, including diabetes and inflammation.

Aim Of The Study: To assure the safety of the botanicals finished products, herb-drug interaction potential of T. crispa and T. sinensis was investigated by testing their extracts and compounds for in vitro activation of the pregnane X-receptor (PXR) and the modulation of CYP3A4 isozyme, selectively.

Materials And Methods: A total of sixteen fully characterized phytochemicals from T. crispa and T. sinensis were evaluated for PXR activation by luciferase reporter gene assay. CYP3A4 inhibition studies were carried out for eleven compounds. In addition, docking studies were performed to elucidate the possible binding modes to the PXR by the compounds using computational methods.

Results: Significant activation of PXR (2-fold) was observed for both extracts and non-polar fractions of T. crispa. Among the pure compounds, columbin showed highest activation of PXR (3-fold), which was comparable with the positive control, rifampicin. Vital interactions were predicted with docking simulation of PXR-columbin complex with critical amino acid residues (Trp-299) that are known for the activation of PXR. The methanolic extracts of T. crispa and T. sinensis also showed considerable CYP3A4 inhibition.

Conclusion: T. crispa and T. sinensis, both demonstrated the potential to mediate herb-drug interaction through PXR activation and inhibition of CYP3A4 isozyme. Moreover, the elucidation of the potential to induce herb-drug interaction, by the phytochemicals of these Tinospora plants, thereby supports the need for further investigation to establish the clinical relevancy of these constituents for possible adverse interactions with pharmaceutical drugs.