Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase

John T Barr; Jeffrey P Jones

doi:10.1124/dmd.112.048546

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Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase

Journal article

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Peer reviewed

Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase

John T Barr and Jeffrey P Jones

Drug metabolism and disposition, Vol.41(1), pp.24-29

01/2013

DOI: https://doi.org/10.1124/dmd.112.048546

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https://hdl.handle.net/2376/107038

PMCID: PMC3533431

PMID: 22996261

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https://doi.org/10.1124/dmd.112.048546View

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Abstract

Aldehyde Oxidase - antagonists & inhibitors

Aminoacridines - pharmacology

Liver - enzymology

Magnetic Resonance Spectroscopy

Oxidation-Reduction

Humans

Mass Spectrometry

Aldehyde Oxidase - metabolism

Enzyme Inhibitors - pharmacology

Chromatography, Liquid

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 V(max) of 2.3 ± 0.08 nmol product · min(-1) · mg(-1) and a K(m) of 6.3 ± 0.8 µM. The K(ii) and K(is) 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 K(ii) value), whereas the competitive mode (K(is)) 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.

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Title: Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase
Creators: John T Barr - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Jeffrey P Jones
Publication Details: Drug metabolism and disposition, Vol.41(1), pp.24-29
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 GM100874 / NIGMS NIH HHS GM100874 / NIGMS NIH HHS
Identifiers: 99900546821601842
Language: English
Resource Type: Journal article