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

Drug Metab Dispos. 2016 Apr;44(4):534-43. doi: 10.1124/dmd.115.067942. Epub 2016 Feb 5.


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. IC50 values from recombinant enzymes indicated that an interaction is most probable for CYP2A6 (IC50 = 6.1 µM). t-CA was 10.5-fold more selective for human CYP2A6 than for CYP2E1; IC50 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 (KS = 14.9 µM). 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 µM; k(inact) = 0.056 minute(-1)), changes in the area under the concentration-time curve (AUC) for nicotine and letrozole were predicted in the presence of t-CA (0.1 and 1 µM). The AUC fold-change ranged from 1.1 to 3.6. In summary, t-CA is a potential source of pharmacokinetic variability for CYP2A6 substrates due to metabolism-dependent inhibition, especially in scenarios when exposure to t-CA is elevated due to high dietary exposure, or when cinnamon is used as a treatment of specific disease states (e.g., diabetes).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / analogs & derivatives*
  • Acrolein / metabolism
  • Acrolein / pharmacology
  • Cytochrome P-450 CYP2A6 / antagonists & inhibitors*
  • Cytochrome P-450 CYP2A6 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Letrozole
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism*
  • Nicotine / metabolism*
  • Nitriles / metabolism*
  • Triazoles / metabolism*


  • Enzyme Inhibitors
  • Nitriles
  • Triazoles
  • Nicotine
  • Acrolein
  • Letrozole
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • cinnamaldehyde