Cannabinoid Inhibition of Carboxylesterase 1 (CES1)

Abstract

The increasing use of cannabis for both medical indications and on a recreational basis poses a potential for drug interactions between cannabis or one or more of its constituents and conventional therapeutic agents. Although significant efforts have been made to assess the in vitro and in vivo effects of cannabis on cytochrome P450 and UDP‐glucuronosyltransferase enzyme systems, there is no information on the potential influence of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the major cannabinoids and metabolites including Δ9‐tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11‐nor‐Δ9‐tetrahydrocannabinol‐carboxylic acid (THC‐COOH), and 11‐Hydroxy‐Δ9‐tetrahydrocannabinol (11‐OH‐THC) on CES1 activity.An in vitro system of S9 fractions from human embryonic kidney (HEK 293) cells stably expressing CES1 was utilized to assess the inhibitory effects of the cannabinoids. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitive‐noncompetitive mechanism. The Ki values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 μM (0.170, 0.306, and 0.0817 μg/ml), respectively. Compared to the unbound plasma concentrations achievable through medical or recreational use, the Ki values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have limited impact on CES1. Clinical studies are warranted to confirm these in vitro findings.Support or Funding InformationSelf‐fundedThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.