Cannabinoids may change how the liver processes medicines

The legalization of cannabis in many parts of the USA and worldwide emphasizes the need to study their potential for interaction with drugs. The Cannabis sativa plant contains over 120 phytocannabinoids, with delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) being the most abundant cannabinoids. The aim of this study was to investigate the effect of treatment with individual cannabinoids or mixture of cannabinoids (mix) on the activity and expression of several cytochrome P450 (CYP) enzymes. Primary cultures of human hepatocytes were pretreated with either vehicle or cannabinoids, followed by incubation with a cocktail of CYP substrates. The activity of various CYP enzymes was determined by quantifying the formation of the metabolites of specific CYP substrates using liquid chromatography-tandem mass spectrometry. The messenger RNA (mRNA) expression of various CYP enzymes was determined by quantitative real-time polymerase chain reaction (qrt-PCR). A significant (> 2-fold) increase in CYP1A2 activity was observed after chronic exposure to CBN and mix at 3 µM. Similarly, THC and mix treatments at 3 µM led to a significant (> 2-fold) increase in CYP3A4 activity and expression. No major inducive effects were observed on CYP2D6 and CYP2C9. Acute exposure to CBD, CBN, or mix inhibited CYP1A2 activity in a concentration-dependent manner; mix showed mild CYP3A4 inhibition at 3 µM with no major effects on CYP2D6 and CYP2C9 activity. These data suggest that cannabinoids selectively alter the activity and expression of CYP enzymes, which may lead to change in exposure of coadministered substrates owing to possible metabolic drug-drug interactions (DDI).