Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Abstract

Human exposure to trans-cinnamic aldehyde [t-CA; cinnamaldehyde; cinnamal; (E)-3-phenylprop-2-enal] is common through diet and through the use of cinnamon powder for diabetes and to provide flavor and scent in commercial products. We evaluated the likelihood of t-CA to influence metabolism by inhibition of P450 enzymes. IC 50 values from recombinant enzymes indicated that an interaction is most probable for CYP2A6 (IC 50 = 6.1 mM). t-CA was 10.5-fold more selective for human CYP2A6 than for CYP2E1; IC 50 values for P450s 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 were 15.8-fold higher or more. t-CA is a type I ligand for CYP2A6 (K S = 14.9 mM). Inhibition of CYP2A6 by t-CA was metabolism-dependent; inhibition required NADPH and increased with time. Glutathione lessened the extent of inhibition modestly and statistically significantly. The carbon monoxide binding spectrum was dramatically diminished after exposure to NADPH and t-CA, suggesting degradation of the heme or CYP2A6 apoprotein. Using a static model and mechanism-based inhibition parameters (K I = 18.0 mM; k inact = 0.056 minute 21

Essential oil components and cytochrome P450 enzymes: a review

“…The effects on CYP2A6 are important to know, as this enzyme is a major clearance route for nicotine and letrozole, which is an aromatase inhibitor used to treat breast cancer. Moreover, the extensive genetic diversity of CYP2A6 can contribute to differences in smoking behaviour or can lead to great differences in steady‐state plasma concentration of letrozole …”

Variation in CYP2A6 Activity and Personalized Medicine

“…However, their relatively low inhibitory potency, and the relatively low levels of each compound in coffee, suggest that they are not likely to substantially inhibit CYP2A6 activity in vivo following typical daily levels of coffee consumption. Additionally, cinnamaldehyde, the primary component of cinnamon that gives it flavour and aroma, acts as a mechanism-based inhibitor of CYP2A6 activity in vitro, as measured by the inhibition of coumarin and letrozole metabolism in human liver microsomes and CYP2A6 supersomes [ 78 ].…”

Mechanisms of Herb-Drug Interactions Involving Cinnamon and CYP2A6: Focus on Time-Dependent Inhibition by Cinnamaldehyde and 2-Methoxycinnamaldehyde

“…Previously, TDI parameters generated using the replot method and a static IVIVE model predicted a 3-fold change in nicotine AUC, with CA as a precipitant (Chan et al, 2016). However, the replot method overlooks several mechanistic complexities observed with P450 kinetics (e.g., multiple ligand binding) and TDI (partial inactivation, reversible MIC formation).…”

“…Reductase. CYP2A6 was expressed and purified as previously reported with some slight modifications (Stephens et al, 2012;Chan et al, 2016). Spectral ligand binding assays, metabolite identification, apoprotein, and heme analysis experiments were conducted using modified recombinant human CYP2A6, which had a N-terminal transmembrane sequence truncation (∆2 -23) and a C-terminal His 4 -tag.…”

“…CA is also often present in fluids for electronic nicotine delivery systems (Behar et al, 2016;Behar et al, 2018). Previously, we observed that CA is a time-dependent inhibitor of CYP2A6 (Chan et al, 2016). Compared to reversible inhibition, timedependent inhibition (TDI) is especially concerning for HDI and drug-drug interactions (DDI) because it can result in prolonged or irreversible inhibition, due to long-lived metabolite-inhibitor complexes (MIC) or enzyme inactivation by metabolites that covalently bind to either the apoprotein or heme prosthetic group essential for enzyme function (Mohutsky and Hall, 2014).…”