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Research ArticleArticle

Inhibition of Human Aldehyde Oxidase Activity by Diet-Derived Constituents: Structural Influence, Enzyme-Ligand Interactions, and Clinical Relevance

John T. Barr, Jeffrey P. Jones, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition January 2015, 43 (1) 34-41; DOI: https://doi.org/10.1124/dmd.114.061192
John T. Barr
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)
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Jeffrey P. Jones
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)
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Nicholas H. Oberlies
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)
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Mary F. Paine
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (J.T.B., M.F.P.); Department of Chemistry, Washington State University, Pullman, Washington (J.P.J.); and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (N.H.O.)
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Abstract

The mechanistic understanding of interactions between diet-derived substances and conventional medications in humans is nascent. Most investigations have examined cytochrome P450–mediated interactions. Interactions mediated by other phase I enzymes are understudied. Aldehyde oxidase (AO) is a phase I hydroxylase that is gaining recognition in drug design and development programs. Taken together, a panel of structurally diverse phytoconstituents (n = 24) was screened for inhibitors of the AO-mediated oxidation of the probe substrate O6-benzylguanine. Based on the estimated IC50 (<100 μM), 17 constituents were advanced for Ki determination. Three constituents were described best by a competitive inhibition model, whereas 14 constituents were described best by a mixed-mode model. The latter model consists of two Ki terms, Kis and Kii, which ranged from 0.26–73 and 0.80–120 μM, respectively. Molecular modeling was used to glean mechanistic insight into AO inhibition. Docking studies indicated that the tested constituents bound within the AO active site and elucidated key enzyme-inhibitor interactions. Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r2 = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure. Finally, a simple static model was used to assess potential clinically relevant AO-mediated dietary substance–drug interactions. Epicatechin gallate and epigallocatechin gallate, prominent constituents in green tea, were predicted to have moderate to high risk. Further characterization of this uncharted type of interaction is warranted, including dynamic modeling and, potentially, clinical evaluation.

Footnotes

    • Received September 16, 2014.
    • Accepted October 16, 2014.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM077482 and R01-GM100874 (M.F.P and J.P.J, respectively)].

  • dx.doi.org/10.1124/dmd.114.061192.

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (1)
Drug Metabolism and Disposition
Vol. 43, Issue 1
1 Jan 2015
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Research ArticleArticle

Inhibition of Aldehyde Oxidase by Dietary Constituents

John T. Barr, Jeffrey P. Jones, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition January 1, 2015, 43 (1) 34-41; DOI: https://doi.org/10.1124/dmd.114.061192

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Research ArticleArticle

Inhibition of Aldehyde Oxidase by Dietary Constituents

John T. Barr, Jeffrey P. Jones, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition January 1, 2015, 43 (1) 34-41; DOI: https://doi.org/10.1124/dmd.114.061192
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