Comparative metabolism of THCA and THCV using UHPLC-Q-Exactive Orbitrap-MS

Abstract

1. Delta(9)-tetrahydrocannabinolic acid (THCA) and delta(9)-tetrahydrocannabivarin (THCV) are phytocannabinoids with a similar structure derived from Cannabis sativa and possess a variety of biological activities. However, the relationship between the metabolic characterisation and bioactivity of THCA and THCV remains elusive.

2. To explore the relationship between the metabolism of THCA and THCV and their underlying mechanism of activity, human/mouse liver microsomes and mouse primary hepatocytes were used to compare the metabolic maps between THCA and THCV through comparative metabolomics. A total of 29 metabolites were identified containing 7 previously undescribed THCA metabolites and 10 previously undescribed THCV metabolites. Of these metabolites, THCA was transformed into an active metabolite of delta(9)-tetrahydrocannabinol (THC) in these three systems, while THCV was transformed into THC and CBD.

3. Bioactivity assays indicated that all of these phytocannabinoids exhibited anti-inflammatory activity, but the effects of THCA and THCV were slightly different in macrophages RAW264.7. Prediction of ADMET lab demonstrated that THCV and its metabolites were endowed with the advantage of blood–brain barrier (BBB) penetration compared to THCA.

4. In conclusion, this study highlighted that metabolism plays a critical role in the biological activity of phytocannabinoids.

Keywords:

• Delta(9)-tetrahydrocannabinolic acid
• delta(9)-tetrahydrocannabivarin
• tetrahydrocannabinol
• comparative metabolism
• UHPLC-Q-Exactive MS

Acknowledgements

We would also like to thank XinChuan Advanced Mass Spectrometry Center of West China Hospital for LC-MS tests.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Key Research and Development Program of China (2021YFF0702003), 1.3.5 Project for Disciplines of Excellence from West China Hospital, “the Fundamental Research Funds for the Central Universities (2022SCU12054)”, “Post-Doctor Research Project, West China Hospital, Sichuan University (2021HXBH041)”.