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Rapid CommunicationShort Communication

Evidence for Substrate-Dependent Inhibition Profiles for Human Liver Aldehyde Oxidase

John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition January 2013, 41 (1) 24-29; DOI: https://doi.org/10.1124/dmd.112.048546
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

The goal of this study was to provide a reasonable assessment of how probe substrate selection may impact the results of in vitro aldehyde oxidase (AO) inhibition experiments. Here, we used a previously studied set of seven known AO inhibitors to probe the inhibition profile of a pharmacologically relevant substrate N-[(2-dimethylamino)ethyl]acridine-4-carboxamide (DACA). DACA oxidation in human liver cytosol was characterized with a measured Vmax of 2.3 ± 0.08 nmol product · min−1 · mg−1 and a Km of 6.3 ± 0.8 µM. The Kii and Kis values describing the inhibition of DACA oxidation by the panel of seven inhibitors were tabulated and compared with previous findings with phthalazine as the substrate. In every case, the inhibition profile shifted to a much less uncompetitive mode of inhibition for DACA relative to phthalazine. With the exception of one inhibitor, raloxifene, this change in inhibition profile seems to be a result of a decrease in the uncompetitive mode of inhibition (an affected Kii value), whereas the competitive mode (Kis) seems to be relatively consistent between substrates. Raloxifene was found to inhibit competitively when using DACA as a probe, and a previous report showed that raloxifene inhibited uncompetitively with other substrates. The relevance of these data to the mechanistic understanding of aldehyde oxidase inhibition and potential implications on drug-drug interactions is discussed. Overall, it appears that the choice in substrate may be critical when conducting mechanistic inhibition or in vitro drug-drug interactions prediction studies with AO

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences (Grant GM100874).

  • dx.doi.org/10.1124/dmd.112.048546.

  • Received August 16, 2012.
  • Accepted September 20, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Rapid CommunicationShort Communication

Substrate-Dependent Inhibition of AO

John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition January 1, 2013, 41 (1) 24-29; DOI: https://doi.org/10.1124/dmd.112.048546

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Rapid CommunicationShort Communication

Substrate-Dependent Inhibition of AO

John T. Barr and Jeffrey P. Jones
Drug Metabolism and Disposition January 1, 2013, 41 (1) 24-29; DOI: https://doi.org/10.1124/dmd.112.048546
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