Differences in aldehyde oxidase activity in cytosolic preparations of human and monkey liver

Sugihara, Kazumi; Kawa, Shigeyuki; Tatsumi, Kiyoshi; Asahara, Toshimasa; Dohi, Kiyohiko

doi:10.1080/15216549700202241

Cited by 29 publications

(31 citation statements)

References 9 publications

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“…Further characterization of aldehyde oxidase in these liver cytosols was conducted by Western blot analysis using aldehyde oxidase antibody. The pattern is similar to the reported data (Sugihara et al, 1997) and shows that human liver-type aldehyde oxidase was present in the chimeric mice (Fig. 2).…”

Section: Characterization Of Aldehyde Oxidase In Chimeric Mousesupporting

confidence: 80%

“…In humans, subtypes of aldehyde oxidase have not been identified, though bands found by Western blot analysis of liver cytosol in human and chimeric mice using aldehyde oxidase antibody may be due to human subtypes. We found two main and two minor bands of aldehyde oxidase by Western blot analysis of aldehyde oxidase in human and monkey livers (Sugihara et al, 1997). It is also important to consider the source of hepatocyte used to prepare chimeric mice, because interindividual variations of aldehyde oxidase activity are known to occur in humans (Rodrigues, 1994;Sugihara et al, 1997;Tayama et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…We found two main and two minor bands of aldehyde oxidase by Western blot analysis of aldehyde oxidase in human and monkey livers (Sugihara et al, 1997). It is also important to consider the source of hepatocyte used to prepare chimeric mice, because interindividual variations of aldehyde oxidase activity are known to occur in humans (Rodrigues, 1994;Sugihara et al, 1997;Tayama et al, 2007). Chimeric mice should be a useful model for predicting drug metabolism in humans, but the role of enzyme activity in extrahepatic organs must be taken into account.…”

Section: Discussionmentioning

confidence: 99%

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Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

Kawa¹,

Nitta²,

Tayama³

et al. 2008

Drug Metabolism and Disposition

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ABSTRACT:Aldehyde oxidase-mediated oxidation of N 1 -methylnicotinamide to N 1 -methyl-2-pyridine-5-carboxamide (2-PY) and N 1 -methyl-4-pyridone-5-carboxamide (4-PY) in chimeric mice constructed by transplanting human hepatocytes into urokinase-type plasminogen activator-transgenic severe combined immunodeficient mice was examined in vivo and in vitro. The activity in liver cytosol of chimeric mice with a high replacement index was approximately 4-fold higher than that in control mice. Furthermore, the oxidation products in control mice were 2-PY and 4-PY, whereas, in chimeric mice, the major product was 2-PY, as in humans. The aldehyde oxidase in chimeric mouse liver was confirmed to be of human type by immunoblotting analysis. The ratio of pyridones (2-PY/4-PY) excreted in the urine of chimeric mice was closer to that of humans than to that of control mice. Thus, the aldehyde oxidase in chimeric mice has human-type functional characteristics. Tateno et al. (2004) established chimeric mice in which the liver was almost completely repopulated with human hepatocytes. Such mice should be an excellent in vivo model for predicting drug metabolism, drug-drug interactions, drug induction, and inhibition of drug-metabolizing enzymes in humans. Katoh et al. (2004Katoh et al. ( , 2005b reported that the patterns of cytochrome P450 isoforms and phase II enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, N-acetyltransferase, and glutathione S-transferase, in chimeric mice having a nearly 90% replacement rate with human hepatocytes were almost identical with those in human liver, and they used these mice to estimate the in vivo induction of cytochrome P450 enzymes in humans (Katoh et al., 2005a). Nishimura et al. (2005) reported that hepatocytes from chimeric mice with nearly completely humanized liver are useful for predictive screening of the induction potency of new drugs on drug-metabolizing enzymes in humans. We were interested in knowing whether drug metabolism by a cytosolic drugmetabolizing enzyme, aldehyde oxidase, in these mice is also similar to that in humans.Aldehyde oxidase (EC 1.2.3.1) contains flavin adenine dinucleotide, molybdenum, and iron-sulfur centers. It has been suggested to be relevant to the pathophysiology of a number of clinical disorders (Berger et al., 1995;Wright et al., 1995;Moriwaki et al., 1997). The enzyme in liver of various species catalyzes the oxidation of various aldehydes and nitrogenous heterocyclic xenobiotics, such as methotrexate and cyclophosphamide (Beedham, 1985;Kitamura et al., 2006), and also catalyzes the metabolism of physiological compounds, such as retinaldehyde (Huang and Ichikawa, 1994). However, there are marked species differences and strain differences of the enzyme activities for oxidative reaction in rats and mice (Beedham, 1985;Schofield et al., 2000;Kitamura et al., 2006;Sugihara et al., 2006). This has presented problems in preclinical studies. Many aldehyde oxidase substrates, such as methotrexate and phthalazine, show similar metabolic profiles ...

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Section: Characterization Of Aldehyde Oxidase In Chimeric Mousesupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

Kawa¹,

Nitta²,

Tayama³

et al. 2008

Drug Metabolism and Disposition

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“…AO catalyzes the oxidation of a number of aldehydes as well as nitrogen containing heterocyclic xenobiotics and drug molecules such as methotrexate, cyclophosphamide, acyclovir, famciclovir, and zaleplon (Kitamura et al, 2006;Pryde et al, 2010). However, in the presence of an electron donor, both AO and XO can catalyze reduction as well, using a variety of substrates such as sulfoxides, N-oxides, nitrosamines, hydroxamic acids, azo-dyes, and oxime derivatives (Tatsumi et al, 1983;Sugihara et al, 1997;Kitamura et al, 2006;Pryde et al, 2010), albeit oxidation reactions are far more common. In general, AO has the ability to oxidize a broader range of substrates than XO.…”

Section: Introductionmentioning

confidence: 99%

A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase

Arora

Philip

Huang

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:The ring oxidation of 2H-oxazole, or C2-unsubstituted oxazole, to 2-oxazolone, a cyclic carbamate, was observed on various 4-or 5-substituted oxazoles. Using 5-(3-bromophenyl)oxazole as a model compound, its 2-oxazolone metabolite M1 was fully characterized by liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance. The reaction mainly occurred in the liver cytosolic fraction without the requirement of cytochrome P450 enzymes and cofactor NADPH. Investigations into the mechanism of formation of 2-oxazolone using various chemical inhibitors indicated that the reaction was primarily catalyzed by aldehyde oxidase and not by xanthine oxidase. In addition, cytosol incubation of 5-(3-bromophenyl)oxazole in the medium containing H 2 18 O led to the 18 O incorporation into M1, substantiating the reaction mechanism of a typical molybdenum hydroxylase. The rank order of liver cytosols for the 2-oxazolone formation was mouse > monkey Ͼ Ͼ rat and human liver cytosol, whereas M1 was not formed in dog liver cytosol. Because the reaction was observed with a number of 4-or 5-substituted 2H-oxazoles in mouse liver cytosols, 2H-oxazoles represent a new substrate chemotype for ring oxidation catalyzed by aldehyde oxidase.

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“…3,6,12,19) In monkeys, which are often used as a model animal for human therapy, aldehyde oxidase activity in liver cytosol was observed as phthalazine, benzaldehyde or N 1 -methylnicotinamide oxidase activity. 10,23,24) However, the drug-reductase activity catalyzed by this enzyme in monkeys has not been reported. In this study, the drug-reducing activity of aldehyde oxidase in monkey liver was examined using zonisamide, sulindac and imipramine N-oxide as substrates.…”

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confidence: 99%

Extremely High Drug-Reductase Activity Based on Aldehyde Oxidase in Monkey Liver.

Kawa

Nakatani

Ohashi

et al. 2001

Biological & Pharmaceutical Bulletin

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The pharmacological action and duration of action of a drug are closely related to the metabolism. For example, the reduction of zonisamide, an anticonvulsant, to 2-sulfamoylacetylphenol (SMAP) is a detoxification reaction, and the reductive ring-opening reaction is catalyzed by aldehyde oxidase and cytochrome P450. [1][2][3] In contrast, the reduction of sulindac, an anti-inflammatory agent, to sulindac sulfide is an activation step, and is catalyzed by aldehyde oxidase, but not cytochrome P450. 4,5) Imipramine N-oxide is also reduced to an active parent drug, imipramine by aldehyde oxidase and cytochrome P450 (Fig. 1). 6,7) Aldehyde oxidase (EC 1.2.3.1), a cytosolic enzyme, contains FAD, molybdenum and iron-sulfur center, and is closely related to xanthine oxidase. 8,9) The enzyme can catalyze the oxidation of a number of aldehydes and nitrogenous heterocyclic compounds. 8,9) In humans, benzaldehyde and N 1 -methylnicotinamide oxidase activities based on aldehyde oxidase were reported. 10,11) Moreover, the enzyme in the presence of its electron donor can mediate the reduction of a variety of compounds such as sulfoxides, 5) N-oxides, 6,12) nitrosamines, 13) hydroxamic acids, 14,15) azo dyes, 16,17) oximes, 18) epoxides, 19) aromatic nitro compounds 20,21) and 1,2-benzisoxazole derivatives. 3) However, it has been reported that a marked species difference exists in the oxidase activity of the enzyme. 8,9) For example, high aldehyde oxidase activity is observed in rabbit and guinea pig livers. 8,9,22) In contrast, aldehyde oxidase activity is not detected in dogs. We also showed a marked species difference of the reductase activity of the enzyme. High reductase activity towards N-oxide compounds, epoxides and 1,2-benzoisoxazole derivatives was observed in rabbits. In contrast, relatively low activity was observed in rats and mice. 3,6,12,19) In monkeys, which are often used as a model animal for human therapy, aldehyde oxidase activity in liver cytosol was observed as phthalazine, benzaldehyde or N 1 -methylnicotinamide oxidase activity. 10,23,24) However, the drug-reductase activity catalyzed by this enzyme in monkeys has not been reported. In this study, the drug-reducing activity of aldehyde oxidase in monkey liver was examined using zonisamide, sulindac and imipramine N-oxide as substrates. * To whom correspondence should be addressed. e-mail: kitamura@pharm.hiroshima-u.ac. 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Received January 18, 2001; accepted May 7, 2001 Drug-reducing ability of monkey liver cytosol was examined in this study. Monkey liver cytosol exhibited significant reductase activities toward zonisamide, sulindac and imipramine N-oxide in the presence of 2-hydroxypyrimidine or benzaldehyde, an electron donor to aldehyde oxidase. These activities were abolished by inhibitors of aldehyde oxidase, such as menadione. These reductase activities in monkeys were extremely high compared to those in other animals. The zonisamide reductase activity of monkey liver cytosol was about 40-fold h...

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Differences in aldehyde oxidase activity in cytosolic preparations of human and monkey liver

Cited by 29 publications

References 9 publications

Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

Aldehyde Oxidase-Catalyzed Metabolism of N1-Methylnicotinamide in Vivo and in Vitro in Chimeric Mice with Humanized Liver

A Novel Ring Oxidation of 4- or 5-Substituted 2H-Oxazole to Corresponding 2-Oxazolone Catalyzed by Cytosolic Aldehyde Oxidase

Extremely High Drug-Reductase Activity Based on Aldehyde Oxidase in Monkey Liver.

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