The oxidation of azaheterocycles with mammalian liver aldehyde oxidase

Stubley, C.; Stell, J. G. P.; Mathieson, D. W.

doi:10.3109/00498257909087261

Cited by 52 publications

(43 citation statements)

References 27 publications

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“…phthalazine and purines), and aromatic or non-aromatic charged heterocycles with -CH=N + -(e.g. N I -methylnicotinamide and N-methylphthalazinium) [13][14][15]. AO also plays a major role in nitroreduction [16] and participates in the reduction of isoxazole and isothiazole ring systems [17].…”

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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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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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“…Similarly excretion of HPZ would be expected to be greater in slow acetylators, and therefore chemical breakdown of this unstable metabolite would also give rise to more PZ in the slow acetylators. However PZ may also arise directly from hydralazine by oxidative metabolism (Streeter, unpublished results) and could also be produced from phthalazine by the action of aldehyde oxidase (Stubley, Stell & Mathieson, 1979). Any of these routes would be expected to yield more PZ in the slow acetylator phenotype.…”

Section: Discussionmentioning

confidence: 99%

Further evidence for an acetylator phenotype difference in the metabolism of hydralazine in man.

Facchini¹,

Timbrell²

1981

Brit J Clinical Pharma

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1 The 0-24 h urine from hypertensive patients treated with hydralazine (100 mg twice daily) has been analysed by gas chromatography and high pressure liquid chromatography. 2 4-N-Acetylhydrazinophthalazine-1-one (NAcHPZ), s-triazolo [3,4-a] phthalazine (TP), phthalazinone (PZ) and hydralazine (free, H; acid-labile hydrazones, HH) were detected and assayed. 3 The results indicate that slow acetylators excrete less NAcHPZ and TP than rapid acetylators but more PZ and HH. 4 Free hydralazine was present in low levels and was only detected in some urine samples. 5 The ratios of the metabolites NAcHPZ/HH; TP/HH; NAcHPZ/PZ and PZ/TP are different in the two acetylator phenotypes. 6 It is possible the ratio PZ/TP may be used for determination of acetylator phenotype. 7 It is concluded that hydralazine metabolism is dependent on the acetylator phenotype.

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“…Although AO has long been known to oxidize nitrogen-containing heterocycles (Knox, 1946;Stanulovi c and Chaykin, 1971;Stubley et al, 1979), its importance to drug metabolism first emerged in the case of carbazeran, a phosphodiesterase-2 inhibitor discontinued due to low oral bioavailability and short half-life in humans (Kaye et al, 1984(Kaye et al, , 1985. Based on analysis of chemical structure, a recent review suggested that a large number of drugs on the market (;13%) or candidate drugs (almost 45% of drugs in development) could be AO substrates (Pryde et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Oxidase Activity in Fresh Human Skin

et al. 2014

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Human aldehyde oxidase (AO) is a molybdoflavoenzyme that commonly oxidizes azaheterocycles in therapeutic drugs. Although high metabolic clearance by AO resulted in several drug failures, existing in vitro-in vivo correlations are often poor and the extrahepatic role of AO practically unknown. This study investigated enzymatic activity of AO in fresh human skin, the largest organ of the body, frequently exposed to therapeutic drugs and xenobiotics. Fresh, full-thickness human skin was obtained from 13 individual donors and assayed with two specific AO substrates: carbazeran and zoniporide. Human skin explants from all donors metabolized carbazeran to 4-hydroxycarbazeran and zoniporide to 2-oxo-zoniporide. Average rates of carbazeran and zoniporide hydroxylations were 1.301 and 0.164 pmol×mg skin, resulting in 13 and 2% substrate turnover, respectively, after 24 hours of incubation with 10 mM substrate. Hydroxylation activities for the two substrates were significantly correlated (r 2 = 0.769), with interindividual variability ranging from 3-fold (zoniporide) to 6-fold (carbazeran). Inclusion of hydralazine, an irreversible inhibitor of AO, resulted in concentration-dependent decrease of hydroxylation activities, exceeding 90% inhibition of carbazeran 4-hydroxylation at 100 mM inhibitor. Reaction rates were linear up to 4 hours and well described by MichaelisMenten enzyme kinetics. Comparison of carbazeran and zoniporide hydroxylation with rates of triclosan glucuronidation and sulfation and p-toluidine N-acetylation showed that cutaneous AO activity is comparable to tested phase II metabolic reactions, indicating a significant role of AO in cutaneous drug metabolism. To our best knowledge, this is the first report of AO enzymatic activity in human skin.

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The oxidation of azaheterocycles with mammalian liver aldehyde oxidase

Cited by 52 publications

References 27 publications

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

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

Further evidence for an acetylator phenotype difference in the metabolism of hydralazine in man.

Aldehyde Oxidase Activity in Fresh Human Skin

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