Cytosolic Enzymes Generate Cannabinoid Metabolites 7-Carboxycannabidiol and 11-Nor-9-carboxytetrahydrocannabinol

Abstract

The cannabinoids cannabidiol (CBD) and delta-9tetrahydrocannabinol (THC) undergo extensive oxidative metabolism in the liver. Although cytochromes P450 form the primary, pharmacologically active, hydroxylated metabolites of CBD and THC, less is known about the enzymes that generate the major in vivo circulating metabolites of CBD and THC, 7-carboxy-CBD and 11-carboxy-THC, respectively. The purpose of this study was to elucidate the enzymes involved in forming these metabolites.Cofactor dependence experiments with human liver subcellular fractions revealed that 7-carboxy-CBD and 11-carboxy-THC formation is largely dependent on cytosolic NAD + -dependent enzymes, with lesser contributions from NADPH-dependent microsomal enzymes. Experiments with chemical inhibitors provided evidence that 7-carboxy-CBD formation is mainly dependent on aldehyde dehydrogenases and 11-carboxy-THC formation is mediated also in part by aldehyde oxidase. This study is the first to demonstrate the involvement of cytosolic drug-metabolizing enzymes in generating major in vivo metabolites of CBD and THC and addresses a knowledge gap in cannabinoid metabolism.

CBD and THC in Special Populations: Pharmacokinetics and Drug–Drug Interactions

“…7-OH-CBD is further metabolized to the inactive 7-COOH-CBD. The primary metabolizing enzyme for this step remains unidentified, although recent evidence suggests that both CYP and aldehyde dehydrogenase (ALDH) enzymes are involved [ 79 ]. 7-OH-CBD and 7-COOH-CBD can undergo glucuronidation in phase II metabolism, but the specific UGTs that are involved require further study.…”

“…The major metabolizing enzymes and metabolites of THC are summarized in Table 1 . A portion of the active main metabolite, 11-OH-THC, undergoes glucuronidation by UGT1A1 and UGT1A3 in the phase II metabolism [ 41 , 79 , 83 , 84 ]. The metabolite 11-COOH-THC is a substrate of the UGT1A family, primarily UGT1A9 and UGT1A10, in phase II metabolism [ 38 ].…”

“…Metabolites CBD Primary: 7-OH-CBD by CYP2C9 and CYP2C19; active [37,78]; Secondary: 7-COOH-CBD, enzyme unidentified; inactive [79].…”

Therapeutic Potential of Methotrexate-Loaded Superparamagnetic Iron Oxide Nanoparticles Coated with Poly(lactic-co-glycolic acid) and Polyethylene Glycol against Breast Cancer: Development, Characterization, and Comprehensive In Vitro Investigation

“…Reactive Oxygen Species. The MCF-7 cells were cultured and subjected to treatment with IC 50 doses of the samples, followed by an incubation period of 24 h. 23 Following incubation, the medium was extracted, and the cells were collected through trypsin EDTA and subsequently gathered in a 1.5 mL tube. The cells were then rinsed once with 500 μL of chilled PBS.…”

Development and Scale-Up of 7-COOH CBD Synthesis, a Key Cannabinoid Metabolite

“…CBD is metabolized primarily by CYP450s, giving rise to several oxidative products, examples of which are shown in Figure . − The principal route of CBD metabolism in humans is via oxidation at the 7-position, driven by CYP3A4 and 2C19, to give 7-CH 2 OH CBD . This compound can be further oxidized to the 7-carboxy species, which is the main metabolite observed in circulation in human plasma. ,− …”