Wednesday, April 2, 2025
4/2/2025
Investigating the Human Metabolism of the Minor Cannabinoid Cannabichromene - PROPOSAL SUMMARY (ABSTRACT) Following federal legalization of hemp and cannabinoids in 2018, as defined by <0.3% Δ9-tetrahydrocannabinol (Δ9-THC), use of minor cannabinoids has grown exponentially. Minor cannabinoids are considered cannabis- derived cannabinoids that are not Δ9-THC or cannabidiol (CBD). Currently, the most popular, and in highest abundance in the cannabis plant include cannabinol, cannabigerol, and cannabichromene (CBC). Importantly, these compounds are available in highly purified and concentrated amounts. CBC in particular is gaining in popularity due to anecdotal claims of anti-inflammatory, anti-tumor, and anti-depressant properties. Due to its recent legalization, comprehensive scientific literature investigating these claims and fundamental pharmacokinetic characteristics are lacking, and it is the goal of this proposal to address this gap in knowledge. Knowing Δ9-THC and CBD metabolites remain biologically active, we will characterize the metabolism of CBC and determine subsequent activity of the metabolites. Our preliminary data suggests the major phase I oxidative metabolite of CBC is the result of a cytochrome P450 (CYP)-mediated epoxidation and subsequent intramolecular rearrangement into 2’-hydroxycannabicitran. The kinetics of this reaction are unknown and therefore the reactivity of CBC metabolism requires further investigation. These initial findings support the notion that CBC pharmacology is complex, but by dissecting metabolism, novel therapeutic modalities limiting toxicological impacts will be identified. The goal of this proposal is to define the metabolic profile of CBC and characterize the biologic activity of CBC and its major metabolites to reveal potential therapeutic or toxicological aspects of this minor cannabinoid. It is our working hypothesis that CBC is heavily metabolized into both phase I- and phase II-type metabolites. We further hypothesize that these metabolites are biologically active and have potential to contribute to metabolizing enzyme inhibition and/or physiological effects of CBC. Through the utilization of translationally relevant systems, namely immortalized human hepatocyte/cholangiocyte cocultures (HepaRG cells), we will identify the human metabolites of CBC in vitro (Aim 1). In Aim 2, we will phenotype metabolizing enzymes (recombinant human CYP450s and uridine 5'-diphospho-glucuronosyltransferase (UGTs)) responsible for the production of major metabolites identified from Aim 1. Further, we will determine if CBC can cause drug-drug interactions and hepatocellular toxicity. We will then characterize the activity of the metabolites in the endocannabidome in silico and through in vitro assays (Aim 3). Taken together, these studies will reveal novel CBC metabolites, determine risk for drug-drug interactions, provide a basis for CBC metabolite activity, and impact safety guidelines in the future.
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