Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase

Kanika V Choughule; John T Barr; Jeffrey P Jones

doi:10.1124/dmd.113.052985

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$Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase$

Journal article

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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, Vol.41(10), pp.1852-1858

10/2013

DOI: https://doi.org/10.1124/dmd.113.052985

Handle:

https://hdl.handle.net/2376/100849

PMCID: PMC3781378

PMID: 23918666

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Abstract

Guinea Pigs

Liver - enzymology

Oxidation-Reduction

Humans

Liver - metabolism

Male

Cytosol - enzymology

Phthalazines - metabolism

Macaca mulatta - metabolism

Animals

Aldehyde Oxidase - metabolism

Cytosol - metabolism

Kinetics

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.

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Title: Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase
Creators: Kanika V Choughule - Department of Chemistry, Washington State University, Pullman, Washington
John T Barr
Jeffrey P Jones
Publication Details: Drug metabolism and disposition, Vol.41(10), pp.1852-1858
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 GM100874 / NIGMS NIH HHS GM100874 / NIGMS NIH HHS
Identifiers: 99900546540001842
Language: English
Resource Type: Journal article