Drug-Metabolizing Ability of Molybdenum Hydroxylases

Kawa, Shigeyuki; Sugihara, Kazumi; Ohta, Shigeru

doi:10.2133/dmpk.21.83

Cited by 200 publications

(181 citation statements)

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“…There is also considerable interindividual variation among rat strains 32 and human beings. 33 A Gly110Ser polymorphism that may alter homodimer formation contributes to the observed 20-to 40-fold variation in AOX activity among rat strains. [34][35][36] An allelic difference in human AOX1 (Asn1135Ser), when combined with assessment of thiopurine methyl-transferase activity, has recently been shown to affect azathioprine response in inflammatory bowel disease.…”

Section: Discussionmentioning

confidence: 98%

In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor

Zhang¹,

Liu

Weller³

et al. 2010

Pharmacogenomics J

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The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short halflife and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species.

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Section: Discussionmentioning

confidence: 98%

In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor

Zhang¹,

Liu

Weller³

et al. 2010

Pharmacogenomics J

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“…Similarly the molybdenum hydroxylases AO and XO both play important roles in the metabolism of many exogenous and endogenous compounds. They exhibit oxidative activity towards various heteroxcyclic compounds and aldehydes and the liver cytosol of various mammals also exhibits a significant reductive activity toward nitro, sulfoxide, N-oxide and other moieties catalyzed by AO [30]. The conventionally accepted role of XO is purine catabolism, in which it catalyzes the oxidation of hypoxanthine to xanthine, then to uric acid [30].…”

Section: Cadmium Exposure Alters Oxidative Enzymes O R I G I N a L P mentioning

confidence: 99%

“…They exhibit oxidative activity towards various heteroxcyclic compounds and aldehydes and the liver cytosol of various mammals also exhibits a significant reductive activity toward nitro, sulfoxide, N-oxide and other moieties catalyzed by AO [30]. The conventionally accepted role of XO is purine catabolism, in which it catalyzes the oxidation of hypoxanthine to xanthine, then to uric acid [30]. SO, another molybdoprotein, is involved in the oxidation of endogenous sulphite arising from the degradation of sulphur amino acids [31].…”

Section: Cadmium Exposure Alters Oxidative Enzymes O R I G I N a L P mentioning

confidence: 99%

Alteration in the activity of oxidative enzymes in the tissues of male wistar albino rats exposed to cadmium

Asagba¹

2010

International Journal of Occupational Medicine and Environmental Health

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Objective: The objective of the present study was to investigate the effect of cadmium (Cd) on the activities of some oxidative enzymes [viz Aldehyde oxidase, AO (E.C. 1.2.3.1); Xanthine oxidase, XO (E.C. 1.2.3.2); Sulphite oxidase, SO (E.C.1.8.3.1.); and Monoamine oxidase, MO (E.C. 1.4.3.4)] in the liver and kidney. Materials and methods: Male Wistar albino rats were administered 1, 2 and 4 mg Cd 2+ /kg body weight for one and three months. The activities of the oxidative enzymes were subsequently analyzed in the liver and kidney after both periods of exposure. Results: There was a dose dependent increase in liver and kidney Cd concentration in the test rats as compared to control after both periods of treatment with the liver retaining higher concentration of Cd than the kidney for each of the exposure dose. The oxidative enzymes were decreased in a dose dependent manner in the liver and kidney after both periods of treatment. The percentage inhibition of these enzymes was less in the liver of rats treated with Cd for three months relative to the one month treated rats for each of the exposure dose. Conversely, the inhibition of the activities of these enzymes in the kidney of rats in all the treatment groups was more pronounced after three months relative to the trend in the one month treated rats. However, the activities of the oxidative enzymes were higher in the liver as compared to the kidney in all the treatment groups after both durations of Cd treatment. Conclusion: Based on the results obtained, it can be concluded that the inhibition of the oxidative enzymes by Cd may disturb metabolism of bioactive endogenous substances, exogenous components of food and some xenobiotics.

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“…Among these three types of substrates, aldehydes are converted to the corresponding carboxylic acids and the other two are hydroxylated in the presence of molecular oxygen, which serves as the acceptor of the reducing equivalents thus obtained. However, AO has much wider substrate specificity than xanthine oxidase and can oxidize a wide variety of aldehyde compounds as well as certain drugs of pharmacological and toxicological importance, including the hypnotic agent zaleplon, the antiviral agent famciclovir, the antiepileptic agent zonisamide, the antitumor agents acridine carboxamide and zebularine, the antituberculous agent pyrazinamide and certain cancer-chemotherapeutic agents (e.g., methotrexate, and 6-methylthiopurine) [40,41].AO and XOR are structurally similar but their substrate and inhibitor specificities differ. In spite of their differences in substrate specificity, the properties and immediate environment of the molybdenum center are quite similar although the properties of Fe-S and FAD centers differ significantly in these enzymes [42].…”

mentioning

confidence: 99%

Characterization of superoxide production from aldehyde oxidase: An important source of oxidants in biological tissues

Kundu

Hille

Murugesan

et al. 2007

Archives of Biochemistry and Biophysics

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Aldehyde oxidase, a molybdoflavoenzyme that plays an important role in aldehyde biotransformation, requires oxygen as substrate and produces reduced oxygen species. However, little information is available regarding its importance in cellular redox stress. Therefore, studies were undertaken to characterize its superoxide and hydrogen peroxide production. Aldehyde oxidase was purified to >98% purity and exhibited a single band at ∼290 kDa on native polyacrylamide gradient gel electrophoresis. Superoxide generation was measured and quantitated by cytochrome c reduction and EPR spin trapping with p-dimethyl aminocinnamaldehyde as reducing substrate. Prominent superoxide generation was observed with an initial rate of 295 nmol/min/mg. Electrochemical measurements of oxygen consumption and hydrogen peroxide formation yielded values of 650 nmol/min/mg and 355 nmol/min/mg. In view of the ubiquitous distribution of aldehydes in tissues, aldehyde oxidase can be an important basal source of superoxide that would be enhanced in disease settings where cellular aldehyde levels are increased. KeywordsAldehyde oxidase; Xanthine oxidase; Superoxide; Hydrogen peroxide; Electron paramagnetic resonance; Spin trapping; Cytochrome c reduction; Reactive oxygen species; Free radicals; Oxygen consumption Aldehyde oxidase (AO; EC 1.2.3.1) 1 is a prominent member of the molybdenum hydroxylase family of enzymes, which also includes xanthine oxidoreductase (XOR). XOR has two interconvertible forms, xanthine dehydrogenase (XDH; EC 1.1.1.204) and xanthine oxidase (XO; 1. 1.3.22). Both forms of XOR are involved in the catabolism of purines, * To whom correspondence should be addressed: Davis Heart and Lung Research Institute, 473 W. 12th Ave, Room 110G, The Ohio State University, Columbus, OH 43210. Phone: (614) . E-Mail: Jay.Zweier@osumc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Both XOR and AO are homodimeric consisting of two identical subunits with an approximate molecular mass of 145 kDa each. Each subunit consists of four discrete regions -two N-terminal domains contain distinct [2Fe-2S] centers. A linker peptide connects it to a 40 kDa FAD binding domain that positions the flavin ring in close proximity and a second linker peptide connects the FAD domain with the 85 kDa C-terminal portion of the protein that contains the molybdenum center and the substrate binding pocket [3,4]. The structure of XOR is well conserved among human, chicken, mouse and rat enzymes [5] and the amino acid sequences reveal that the molybdenum binding site is the most conserved region with 94% homo...

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Drug-Metabolizing Ability of Molybdenum Hydroxylases

Cited by 200 publications

References 121 publications

In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor

In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor

Alteration in the activity of oxidative enzymes in the tissues of male wistar albino rats exposed to cadmium

Characterization of superoxide production from aldehyde oxidase: An important source of oxidants in biological tissues

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