ArticleBiochemical pharmacology2015
Interspecies differences in the metabolism of methotrexate: An insight into the active site differences between human and rabbit aldehyde oxidase.
Article in Biochemical pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 32 citations in OpenAlex.
- Evaluation of BCRP-Related DDIs Between Methotrexate and Cyclosporin A Using Physiologically Based Pharmacokinetic Modelling.Drugs in R&D · 2025Article
- Deciphering the cell type-specific and zonal distribution of drug-metabolizing enzymes, transporters, and transcription factors in livers of mice using single-cell transcriptomics.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Simultaneous Determination of Unbound Plasma Concentration of Methotrexate and 7-Hydroxymethotrexate in Children Patients Receiving High-Dose Methotrexate Therapy.Drug design, development and therapy · 2025Article
- Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes.Archives of toxicology · 2024Review
- Article
- Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions.Archives of toxicology · 2022Review
- Enzyme Kinetics, Pharmacokinetics, and Inhibition of Aldehyde Oxidase.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Site-Directed Mutagenesis at the Molybdenum Pterin Cofactor Site of the Human Aldehyde Oxidase: Interrogating the Kinetic Differences Between Human and Cynomolgus Monkey.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Identification and Characterization of Aldehyde Oxidase 5 in the Pheromone Gland of the Silkworm (Lepidoptera: Bombycidae).Journal of insect science (Online) · 2020Article
- A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase.PloS one · 2017Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Several drug compounds have failed in clinical trials due to extensive biotransformation by aldehyde oxidase (AOX) (EC 1.2.3.1). One of the main reasons is the difficulty in scaling clearance for drugs metabolised by AOX, from preclinical species to human. Using methotrexate as a probe substrate, we evaluated AOX metabolism in liver cytosol from human and commonly used laboratory species namely guinea pig, monkey, rat and rabbit. We found that the metabolism of methotrexate in rabbit liver cytosol was several orders of magnitude higher than any of the other species tested. The results of protein quantitation revealed that the amount of AOX1 in human liver was similar to rabbit liver. To understand if the observed differences in activity were due to structural differences, we modelled rabbit AOX1 using the previously generated human AOX1 homology model. Molecular docking of methotrexate into the active site of the enzyme led to the identification of important residues that could potentially be involved in substrate binding and account for the observed differences. In order to study the impact of these residue changes on enzyme activity, we used site directed mutagenesis to construct mutant AOX1 cDNAs by substituting nucleotides of human AOX1 with relevant ones of rabbit AOX1. AOX1 mutant proteins were expressed in Escherichia coli. Differences in the kinetic properties of these mutants have been presented in this study.
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