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Research ArticleArticle

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

Jeannine Chan, Tyler Oshiro, Sarah Thomas, Allyson Higa, Stephen Black, Aleksandar Todorovic, Fawzy Elbarbry and John P. Harrelson
Drug Metabolism and Disposition April 2016, 44 (4) 534-543; DOI: https://doi.org/10.1124/dmd.115.067942
Jeannine Chan
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.)
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Tyler Oshiro
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.)
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Sarah Thomas
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.)
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Allyson Higa
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.)
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Stephen Black
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.)
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Aleksandar Todorovic
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.)
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Fawzy Elbarbry
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.)
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John P. Harrelson
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.)
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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 (KI = 18.0 µM; kinact = 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).

Footnotes

    • Received October 16, 2015.
    • Accepted February 4, 2016.
  • This work was supported by the Medical Research Foundation of Oregon, the M. J. Murdock Charitable Trust, the Pacific Research Institute for Science and Mathematics, and the Pacific University College of Health Professions and School of Pharmacy. The CYP2A6 plasmid, provided as a gift, was supported by the National Institutes of Health [Grant R01 GM076343].

  • dx.doi.org/10.1124/dmd.115.067942.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

CYP2A6 Inhibition by Cinnamic Aldehyde

Jeannine Chan, Tyler Oshiro, Sarah Thomas, Allyson Higa, Stephen Black, Aleksandar Todorovic, Fawzy Elbarbry and John P. Harrelson
Drug Metabolism and Disposition April 1, 2016, 44 (4) 534-543; DOI: https://doi.org/10.1124/dmd.115.067942

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Research ArticleArticle

CYP2A6 Inhibition by Cinnamic Aldehyde

Jeannine Chan, Tyler Oshiro, Sarah Thomas, Allyson Higa, Stephen Black, Aleksandar Todorovic, Fawzy Elbarbry and John P. Harrelson
Drug Metabolism and Disposition April 1, 2016, 44 (4) 534-543; DOI: https://doi.org/10.1124/dmd.115.067942
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