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Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole.
Chan, Jeannine; Oshiro, Tyler; Thomas, Sarah; Higa, Allyson; Black, Stephen; Todorovic, Aleksandar; Elbarbry, Fawzy; Harrelson, John P.
Affiliation
  • Chan J; 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.).
  • Oshiro T; 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.).
  • Thomas S; 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.).
  • Higa A; 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.).
  • Black S; 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.).
  • Todorovic A; 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.).
  • Elbarbry F; 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.).
  • Harrelson JP; 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.
Drug Metab Dispos ; 44(4): 534-43, 2016 Apr.
Article in En | MEDLINE | ID: mdl-26851241
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).
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Triazoles / Acrolein / Microsomes, Liver / Cytochrome P-450 CYP2A6 / Nicotine / Nitriles Type of study: Prognostic_studies Limits: Humans Language: En Journal: Drug Metab Dispos Journal subject: FARMACOLOGIA Year: 2016 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Triazoles / Acrolein / Microsomes, Liver / Cytochrome P-450 CYP2A6 / Nicotine / Nitriles Type of study: Prognostic_studies Limits: Humans Language: En Journal: Drug Metab Dispos Journal subject: FARMACOLOGIA Year: 2016 Type: Article