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Research ArticleArticle

Aldehyde Oxidase Contributes to All-Trans-Retinoic Acid Biosynthesis in Human Liver

Guo Zhong, Chris J. Seaman, Erickson M. Paragas, Huaqing Xi, Karla-Luise Herpoldt, Neil P. King, Jeffrey P. Jones and Nina Isoherranen
Drug Metabolism and Disposition March 2021, 49 (3) 202-211; DOI: https://doi.org/10.1124/dmd.120.000296
Guo Zhong
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Chris J. Seaman
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Erickson M. Paragas
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Huaqing Xi
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Karla-Luise Herpoldt
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Neil P. King
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Jeffrey P. Jones
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Nina Isoherranen
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (G.Z., C.J.S., H.X., N.I.); Department of Chemistry, Washington State University, Pullman, Washington (E.M.P., J.P.J.); and Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington (K.-L.H., N.P.K.)
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Abstract

All-trans-retinoic acid (atRA) is a critical endogenous signaling molecule. atRA is predominantly synthesized from retinaldehyde by aldehyde dehydrogenase 1A1 (ALDH1A1), but aldehyde oxidase (AOX) may also contribute to atRA biosynthesis. The goal of this study was to test the hypothesis that AOX contributes significantly to atRA formation in human liver. Human recombinant AOX formed atRA from retinaldehyde (Km ∼1.5 ± 0.4 µM; kcat ∼3.6 ± 2.0 minute−1). In human liver S9 fractions (HLS9), atRA formation was observed in the absence of NAD+, suggesting AOX contribution to atRA formation. In the presence of NAD+, Eadie-Hofstee plots of atRA formation in HLS9 indicated that two enzymes contributed to atRA formation. The two enzymes were identified as AOX and ALDH1A1 based on inhibition of atRA formation by AOX inhibitor hydralazine (20%–50% inhibition) and ALDH1A1 inhibitor WIN18,446 (50%–80%inhibition). The expression of AOX in HLS9 was 9.4–24 pmol mg−1 S9 protein, whereas ALDH1A1 expression was 156–285 pmol mg−1 S9 protein measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) quantification of signature peptides. The formation velocity of atRA in the presence of NAD+ correlated significantly with the expression of ALDH1A1 and AOX protein. Taken together, the data show that both AOX and ALDH1A1 contribute to atRA biosynthesis in the human liver, with ALDH1A1 being the high-affinity, low-capacity enzyme and AOX being the low-affinity, high-capacity enzyme. The results suggest that in the case of ALDH1A dysfunction or excess vitamin A, AOX may play an important role in regulating hepatic vitamin A homeostasis and that inhibition of AOX may alter atRA biosynthesis and signaling.

SIGNIFICANCE STATEMENT This study provides direct evidence to show that human AOX converts retinaldehyde to atRA and contributes to hepatic atRA biosynthesis. The finding that AOX may be responsible for 20%–50% of overall hepatic atRA formation suggests that alterations in AOX activity via drug-drug interactions, genetic polymorphisms, or disease states may impact hepatic atRA concentrations and signaling and alter vitamin A homeostasis.

Footnotes

    • Received October 25, 2020.
    • Accepted December 3, 2020.
  • This study was supported by National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM111772].

  • https://doi.org/10.1124/dmd.120.000296.

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

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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Research ArticleArticle

Retinoic Acid Synthesis by Aldehyde Oxidase

Guo Zhong, Chris J. Seaman, Erickson M. Paragas, Huaqing Xi, Karla-Luise Herpoldt, Neil P. King, Jeffrey P. Jones and Nina Isoherranen
Drug Metabolism and Disposition March 1, 2021, 49 (3) 202-211; DOI: https://doi.org/10.1124/dmd.120.000296

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Research ArticleArticle

Retinoic Acid Synthesis by Aldehyde Oxidase

Guo Zhong, Chris J. Seaman, Erickson M. Paragas, Huaqing Xi, Karla-Luise Herpoldt, Neil P. King, Jeffrey P. Jones and Nina Isoherranen
Drug Metabolism and Disposition March 1, 2021, 49 (3) 202-211; DOI: https://doi.org/10.1124/dmd.120.000296
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