FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R4072.


Cannabidiol (CBD), a natural product derived from cannabis, was recently FDA-approved to treat epilepsy in children. CBD is extensively metabolized by hepatic cytochrome P450 (P450) enzymes to form the pharmacologically active metabolite 7-hydroxy-cannabidiol (7-OH-CBD). This metabolite is further converted to the major circulating metabolite, 7-carboxy-cannabidiol (7-COOH-CBD), prior to hepatobiliary excretion. CBD is mainly eliminated in the form of 7-COOH-CBD and related hydroxylated derivatives, and the plasma area under the curve of 7-COOH-CBD is up to 40 times higher than that of the parent compound. While prior work has shown that 7-OH-CBD is mainly formed by CYP2C9 and CYP2C19, the enzymes involved in 7-COOH-CBD formation have not been clearly established. Preliminary data from in vitro experiments with hepatocytes and hepatic subcellular fractions suggests that cytosolic enzymes may contribute to formation of 7-COOH-CBD. The objective of this study was to define the roles of P450 versus non-P450 enzymes in 7-COOH-CBD generation. We hypothesized that 7-OH-CBD may be metabolized through a multi-step reaction involving an aldehyde intermediate prior to conversion to 7-COOH-CBD. Reaction phenotyping experiments were performed with 7-OH-CBD and human liver microsomes, cytosol, and S9 fraction in the presence of selective enzyme inhibitors and cofactors to determine their effects on 7-COOH-CBD formation. Results show that 7-COOH-CBD formation is largely NAD+ -dependent, and the cytosolic enzyme aldehyde dehydrogenase can generate 7-COOH-CBD. In addition, reactions performed in the presence of the trapping agent methoxylamine show decreased 7-COOH-CBD formation in human liver S9 fraction compared to those lacking this agent, suggesting that a reactive aldehyde intermediate may be formed from 7-OH-CBD. These data fill a critical research gap in our understanding of cannabinoid metabolism and help identify potential safety risks and drug-drug interactions for patients and consumers taking CBD.

PMID:35554668 | DOI:10.1096/fasebj.2022.36.S1.R4072

Source: ncbi

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