title: 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. 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).
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Jeannine
authors: J
authors: Chan
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Tyler
authors: T
authors: Oshiro
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Sarah
authors: S
authors: Thomas
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Allyson
authors: A
authors: Higa
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Stephen
authors: S
authors: Black
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Aleksandar
authors: A
authors: Todorovic
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.).
authors: Fawzy
authors: F
authors: Elbarbry
authors: Chemistry Department, Pacific University Oregon, Forest Grove, Oregon (J.C., T.O., A.H., S.B.); and School of Pharmacy, Pacific University Oregon, Hillsboro, Oregon (S.T., A.H., S.B., A.T., F.E., J.P.H.) harrelsonj@pacificu.edu.
authors: John P
authors: JP
authors: Harrelson
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D065637:Cytochrome P-450 CYP2A6 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D000077289:Letrozole; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000378:metabolism*; D009570:Nitriles / Q000378:metabolism*; D014230:Triazoles / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009570:Nitriles; D014230:Triazoles; D009538:Nicotine; D000171:Acrolein; D000077289:Letrozole; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C012843:cinnamaldehyde