Interspecies differences in the metabolism of methotrexate: An insight into the active site differences between human and rabbit aldehyde oxidase

Choughule, Kanika V.; Joswig-Jones, Carolyn A.; Jones, Jeffrey P.

doi:10.1016/j.bcp.2015.05.010

Cited by 28 publications

(15 citation statements)

References 30 publications

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“…NADH is found in all living cells and it is the major source of the electrons transported by the mitochondria and responsible for the synthesis of ATP. Hepatic AOX preparations have been shown to oxidize NADH generating the reducing equivalents necessary for O 2 •− production from molecular oxygen [ 19 , 27 , 28 ]. Our results, however, show that hAOX1 does not react with NADH.…”

Section: Discussionmentioning

confidence: 99%

A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase

2017

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Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. The physiological function of mammalian AOX isoenzymes is still unclear, however, human AOX (hAOX1) is an emerging enzyme in phase-I drug metabolism. Indeed, the number of xenobiotics acting as hAOX1 substrates is increasing. Further, numerous single-nucleotide polymorphisms (SNPs) have been identified within the hAOX1 gene. SNPs are a major source of inter-individual variability in the human population, and SNP-based amino acid exchanges in hAOX1 reportedly modulate the catalytic function of the enzyme in either a positive or negative fashion. In this report we selected ten novel SNPs resulting in amino acid exchanges in proximity to the FAD site of hAOX1 and characterized the purified enzymes after heterologous expression in Escherichia coli. The hAOX1 variants were characterized carefully by quantitative differences in their ability to produce superoxide radical. ROS represent prominent key molecules in physiological and pathological conditions in the cell. Our data reveal significant alterations in superoxide anion production among the variants. In particular the SNP-based amino acid exchange L438V in proximity to the isoalloxanzine ring of the FAD cofactor resulted in increased rate of superoxide radical production of 75%. Considering the high toxicity of the superoxide in the cell, the hAOX1-L438V SNP variant is an eventual candidate for critical or pathological roles of this natural variant within the human population.

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Section: Discussionmentioning

confidence: 99%

A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase

2017

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“…Recent evidence has also suggested a role for AOs metabolism in species-dependent metabolic profiles, as observed with methotrexate, GDC-0834, or ripasudil, an inhibitor of Rho-associated coiled coilcontaining protein kinase Choughule et al, 2015;Isobe et al, 2016). In certain cases, specific arguments have been made for the use of higher preclinical species being more relevant to predict human AO metabolism, as in the case of the epidermal growth factor receptor inhibitor BIBX1382 [N 8 - Fig.…”

Section: Aldehyde Oxidases and Xanthine Oxidasesmentioning

confidence: 99%

Cytochrome P450 and Non–Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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“…production from molecular oxygen (Kundu et al, 2007;Maia et al, 2007;Choughule et al, 2015). However, the basis of most of these studies is the use of hepatic cytosolic extracts obtained from rats or rabbits containing mixtures of AOX1 and AOX3.…”

Section: Discussionmentioning

confidence: 99%

Direct Comparison of the Enzymatic Characteristics and Superoxide Production of the Four Aldehyde Oxidase Enzymes Present in Mouse

Kücükgöze

Terao

Garattini

et al. 2017

Drug Metabolism and Disposition

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Aldehyde oxidases (AOXs) are molybdoflavoenzymes with an important role in the metabolism and detoxification of heterocyclic compounds and aliphatic as well as aromatic aldehydes. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. Four different enzymes, mAOX1, mAOX3, mAOX4, and mAOX2, which are the products of distinct genes, are present in the mouse. A direct and simultaneous comparison of the enzymatic properties and characteristics of the four enzymes has never been performed. In this report, the four catalytically active mAOX enzymes were purified after heterologous expression in The kinetic parameters of the four mouse AOX enzymes were determined and compared with the use of six predicted substrates of physiologic and toxicological interest, i.e., retinaldehyde,-methylnicotinamide, pyridoxal, vanillin, 4-(dimethylamino)cinnamaldehyde (DMAC), and salicylaldehyde. While retinaldehyde, vanillin, DMAC, and salycilaldehyde are efficient substrates for the four mouse AOX enzymes,-methylnicotinamide is not a substrate of mAOX1 or mAOX4, and pyridoxal is not metabolized by any of the purified enzymes. Overall, mAOX1, mAOX2, mAOX3, and mAOX4 are characterized by significantly different and values for the active substrates. The four mouse AOXs are also characterized by quantitative differences in their ability to produce superoxide radicals. With respect to this last point, mAOX2 is the enzyme generating the largest rate of superoxide radicals of around 40% in relation to moles of substrate converted, and mAOX1, the homolog to the human enzyme, produces a rate of approximately 30% of superoxide radicals with the same substrate.

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Interspecies differences in the metabolism of methotrexate: An insight into the active site differences between human and rabbit aldehyde oxidase

Cited by 28 publications

References 30 publications

A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase

A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase

Cytochrome P450 and Non–Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Direct Comparison of the Enzymatic Characteristics and Superoxide Production of the Four Aldehyde Oxidase Enzymes Present in Mouse

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