An in vitro evaluation of common botanical extracts on carboxylesterase 1 (CES1) catalytic activity

Carboxylesterase 1 (CES1) is an abundant hepatic drug metabolizing enzyme whose substrates include endogenous compounds and medications from a variety of therapeutic classes. CES1 is a serine hydrolase that catalyzes the cleavage of amides, esters, and thioesters. Concerns have been raised over botanical-drug interactions (BDIs) and their potential to impair enzymatic function resulting in therapeutic failures or adverse effects. BDIs have been extensively investigated with the cytochrome P450 family of enzymes; however, CES1 BDIs have remained largely uninvestigated. This study assessed the CES1 in vitro inhibitory effects of 18 commonly used botanical extracts and their major constituents using an established probe assay and liquid chromatography-tandem mass spectrometry analysis. The following plant extracts demonstrated significant reversible inhibition of CES1 metabolism: ashwagandha, cannabis, saw palmetto, St. John's wort, turmeric, and yohimbe. The following phytochemical constituents demonstrated significant reversible inhibition of CES1: cannabigerol, curcumin, lauric acid, linoleic acid, hypericin, hyperforin, kaempferol, and tetrahydrocannabinolic acid. Tetrahydrocannabinolic acid was the most potent inhibitor of CES1 and displayed a complete mixed competitive-noncompetitive type inhibition. Cannabis, St. John's wort, and turmeric all displayed inhibition potencies (inhibition constants; Kis) of <1 μM relative to their most abundant constituent. Using available pharmacokinetic data, it is anticipated that most extracts and constituents may impact the area under the curve of CES1 substrate medications. However, further in vitro and clinical studies must be conducted to fully elucidate BDI risk through CES1 impairment. SIGNIFICANCE STATEMENT: Carboxylesterase 1, an abundant drug metabolizing enzyme in the liver, metabolizes many drugs, but studies regarding its botanical interaction potential are limited. An in vitro assessment determined the interaction liability between carboxylesterase 1 and botanical products and found some botanicals may pose a concern.