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Research ArticleArticle

Evaluation of Rhesus Monkey and Guinea Pig Hepatic Cytosol Fractions as Models for Human Aldehyde Oxidase

Kanika V. Choughule, John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition October 2013, 41 (10) 1852-1858; DOI: https://doi.org/10.1124/dmd.113.052985
Kanika V. Choughule
Department of Chemistry, Washington State University, Pullman, Washington
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John T. Barr
Department of Chemistry, Washington State University, Pullman, Washington
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Jeffrey P. Jones
Department of Chemistry, Washington State University, Pullman, Washington
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Abstract

Aldehyde oxidase (AOX) is a cytosolic enzyme expressed across a wide range of species, including guinea pig and rhesus monkey. These species are believed to be the best preclinical models for studying human AOX-mediated metabolism. We compared AOX activity in rhesus monkeys, guinea pigs, and humans using phthalazine and N-[2-(dimethylamino)ethyl]acridone-4-carboxamide (DACA) as substrates and raloxifene as an inhibitor. Michaelis-Menten kinetics was observed for phthalazine oxidation in rhesus monkey, guinea pig, and human liver cytosol, whereas substrate inhibition was seen with DACA oxidase activity in all three livers. Raloxifene inhibited phthalazine and DACA oxidase activity uncompetitively in guinea pig, whereas mixed-mode inhibition was seen in rhesus monkey. Our analysis of the primary sequence alignment of rhesus monkey, guinea pig, and human aldehyde oxidase isoform 1 (AOX1) along with homology modeling has led to the identification of several amino acid residue differences within the active site and substrate entrance channel of AOX1. We speculate that some of these residues might be responsible for the differences observed in activity. Overall, our data indicate that rhesus monkeys and guinea pigs would overestimate intrinsic clearance in humans and would be unsuitable to use as animal models. Our study also showed that AOX metabolism in species is substrate-dependent and no single animal model can be reliably used to predict every drug response in humans.

Footnotes

    • Received May 16, 2013.
    • Accepted August 5, 2013.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM100874].

  • dx.doi.org/10.1124/dmd.113.052985.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (10)
Drug Metabolism and Disposition
Vol. 41, Issue 10
1 Oct 2013
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Research ArticleArticle

Page-Species Differences in AOX Activity and Inhibition

Kanika V. Choughule, John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1852-1858; DOI: https://doi.org/10.1124/dmd.113.052985

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Research ArticleArticle

Page-Species Differences in AOX Activity and Inhibition

Kanika V. Choughule, John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1852-1858; DOI: https://doi.org/10.1124/dmd.113.052985
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