The Intracellular Mechanism of Berberine-Induced Inhibition of CYP3A4 Activity

Background: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear re-ceptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. Methods: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. Results: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. Conclusion: These findings may lead to the determination of novel drug-drug interactions with BBR, and con-tribute to future clinical application of BBR.

Automated summary

The study revealed that berberine inhibits the transcription of CYP3A4 gene by downregulating nuclear receptor PXR, and accelerates the degradation of CYP3A4 protein via polyubiquitination pathway. These findings provide insights into the mechanisms of drug-drug interactions involving berberine.