ESTIMATION OF ALDEHYDE OXIDASE ACTIVITY IN VIVO FROM CONVERSION RATIO OF <i>N</i><sup>1</sup>-METHYLNICOTINAMIDE TO PYRIDONES, AND INTRASPECIES VARIATION OF THE ENZYME ACTIVITY IN RATS

Sugihara, Kazumi; Tayama, Yoshitaka; Shimomiya, Kazuhiro; Yoshimoto, Daisuke; Ohta, Shigeru; Kawa, Shigeyuki

doi:10.1124/dmd.105.006544

Cited by 33 publications

(22 citation statements)

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“…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.…”

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confidence: 97%

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 Metab Dispos

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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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confidence: 97%

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 Metab Dispos

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“…[11][12][13][14][15] We demonstrated that an obvious individual difference in AOX1 activity in Donryu strain rats is derived from a single nucleotide substitution of the AOX1 gene consisting of approximately 4300 base pairs. In addition, the mechanism of the individual difference is true to strain differences in rat.…”

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Effects of Selenium Deficiency on Aldehyde Oxidase 1 in Rats

Itoh

Adachi

Sato

et al. 2009

Biological & Pharmaceutical Bulletin

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Aldehyde oxidase 1 (AOX1, EC 1.2.3.1) and xanthine oxidase are major members of the molybdo-flavoenzyme family. Both enzymes consist of a homodimer with a subunit molecular mass of about 150 kDa. AOX1 catalyzes the oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. [1][2][3] The representative N-heterocyclic-containing drugs that serve as substrates for AOX1 are famciclovir, 4) methotrexate, 5) 6-mercaptopurine, 6) and cinchona alkaloids. 7) In addition, the atypical antipsychotic drug, ziprasidone, is mainly metabolized by AOX1-catalyzed reductive ring cleavage in human. 8) Retinal is an aldehyde derivative of vitamin A that is oxidized to transcriptional retinoic acid by retinal oxidase. Retinal oxidase was found to be identical to AOX1. 9) Although retinal can be considered to be a physiological substrate of AOX1, the possibility was doubted by Garattini et al. in mouse liver cytosolic extracts due to higher activity of aldehyde dehydrogenase than that of the combined activities of AOX1 and aldehyde oxidase homologue 1 (AOH1).3) AOX1 might have an indirect role in biogenic neurotransmitter amine metabolism via biotransformation of their oxidatively deaminated intermediate aldehydes to carboxylic acids. 10) Thus, AOX1 is definitely a kind of drug-metabolizing enzyme, but its physiological role has not yet been revealed. AOX1 has some interesting pharmacokinetic properties. It is well known that there are remarkable species differences in AOX1 activity depending on not only animal species but also on the chemical structure of the substrate. Roughly speaking, AOX1 activity is high in monkey and human, moderate to low in rat and mouse, and deficient in dog.1,2) Large strain differences in rat, and individual differences in some kinds of rat strains have also been reported. [11][12][13][14][15] We demonstrated that an obvious individual difference in AOX1 activity in Donryu strain rats is derived from a single nucleotide substitution of the AOX1 gene consisting of approximately 4300 base pairs. In addition, the mechanism of the individual difference is true to strain differences in rat. 16,17) Many drug metabolizing enzymes are generally susceptible to change caused by a variety of internal and external factors. Genetic mutation is one of major internal factors as well as are disease status and age. Nutritional condition is given as an example of an external factor along with enzyme induction and inhibition, which are often caused by concurrently administered medicines, herbs, and foods. As for AOX1, the induction by dioxine 18) and the in vitro inhibition by a number of medicines such as raloxifen and ethinylestradiol 19) have been reported. Furthermore, the amount of retinal oxidase, namely AOX1, has been demonstrated to be increased by zinc deficiency. 20,21) Selenium is an essential trace element similar to zinc. Selenium deficiency has been known to affect drug metabolizing enzymes differently: a severe decrease of Se-dependent glutathione peroxidase (GSH-Px...

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“…The expression and activity of AO in liver of h-PXB mice have been reported (Kitamura et al, 2008). In contrast, the AO activity of r-PXB mice seems to be low, probably because rat hepatocytes for r-PXB mice were derived from Crj:SD rats, which show lower AO activity than other strains of rats (Moriyasu et al, 2006;Sugihara et al, 2006;Itoh et al, 2007). The levels of expression P450 and non-P450 enzymes and metabolic activities in fresh h-hepatocytes are similar to dmd.aspetjournals.org those of actual human hepatocytes (Yoshitsugu et al, 2006;Yamasaki et al, 2010).…”

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confidence: 99%

Prediction of Human Metabolism of FK3453 by Aldehyde Oxidase Using Chimeric Mice Transplanted with Human or Rat Hepatocytes

Sanoh¹,

Nozaki²,

Murai³

et al. 2011

Drug Metab Dispos

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ABSTRACT:During drug development, it is important to predict the activities of multiple metabolic enzymes, not only cytochrome P450 (P450) but also non-P450 enzymes, such as conjugative enzymes and aldehyde oxidase (AO). In this study, we focused on prediction of AO-mediated human metabolism and pharmacokinetics (PK) of 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) (Astellas Pharma Inc.), the development of which was suspended due to extremely low exposure in human, despite good oral bioavailability in rat and dog. We examined species difference in oxidative metabolism of the aminopyrimidine moiety of FK3453, catalyzed by AO, using human-chimeric mice with humanized liver (h-PXB mice) and rat-chimeric mice (r-PXB mice) transplanted with rat hepatocytes. AO activity of h-PXB mouse hepatocytes was higher than that of r-PXB mouse hepatocytes. Moreover, higher concentrations of human-specific AO-generated FK3453 metabolite A-M were detected in urine and feces after administration of FK3453 to h-PXB mice versus r-PXB mice. The total clearance of h-PXB mice was 2-fold higher than that of r-PXB mice. These results agreed reasonably well with the metabolism and PK profiles of FK3453 in human and rat. Our results indicated that h-PXB mice should be helpful for predicting the metabolic profile of drugs in humans, and the use of both h-PXB and r-PXB mice should be helpful for evaluation of species differences of AO metabolic activity.

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ESTIMATION OF ALDEHYDE OXIDASE ACTIVITY IN VIVO FROM CONVERSION RATIO OF N¹-METHYLNICOTINAMIDE TO PYRIDONES, AND INTRASPECIES VARIATION OF THE ENZYME ACTIVITY IN RATS

Cited by 33 publications

References 20 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

Effects of Selenium Deficiency on Aldehyde Oxidase 1 in Rats

Prediction of Human Metabolism of FK3453 by Aldehyde Oxidase Using Chimeric Mice Transplanted with Human or Rat Hepatocytes

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ESTIMATION OF ALDEHYDE OXIDASE ACTIVITY IN VIVO FROM CONVERSION RATIO OF N1-METHYLNICOTINAMIDE TO PYRIDONES, AND INTRASPECIES VARIATION OF THE ENZYME ACTIVITY IN RATS

Cited by 33 publications

References 20 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

Effects of Selenium Deficiency on Aldehyde Oxidase 1 in Rats

Prediction of Human Metabolism of FK3453 by Aldehyde Oxidase Using Chimeric Mice Transplanted with Human or Rat Hepatocytes

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Product

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ESTIMATION OF ALDEHYDE OXIDASE ACTIVITY IN VIVO FROM CONVERSION RATIO OF N¹-METHYLNICOTINAMIDE TO PYRIDONES, AND INTRASPECIES VARIATION OF THE ENZYME ACTIVITY IN RATS

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