Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

Itoh, Kunio; Masubuchi, Akiko; Sasaki, Takuma; Adachi, Mayuko; Watanabe, Nobuaki; Nagata, Kiyoshi; Yamazoe, Yasushi; Hiratsuka, Masahiro; Mizugaki, Michinao; Tanaka, Yorihisa

doi:10.1124/dmd.106.011502

Cited by 21 publications

(20 citation statements)

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“…Similar to those reports, we observed remarkable species differences, rat strain differences, and polymorphism-based individual differences in Donryu strain rat in the AO-catalyzed 2-oxidation activity of the (S)-enantiomer of RS-8359, [(Ϯ)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine]. [14][15][16][17][18] The compound is a reversible and selective monoamine oxidase (MAO)-A inhibitor 19,20) and has been developed as an anti-depressant. 21,22) As to species differences, monkeys showed the highest activity followed by humans.…”

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confidence: 75%

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

Itoh

Asakawa

Hoshino

et al. 2009

Biological & Pharmaceutical Bulletin

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Aldehyde oxidase (AO, EC 1.2.3.1) and xanthine oxidase are major members of the molybdenum hydroxylase family. Both enzymes consist of a homodimer with a subunit molecular mass of about 150 kDa. Each subunit is made up of a 20 kDa domain containing two different 2Fe-2S clusters in which reducing equivalents necessary for catalysis are stored, a 40 kDa domain containing a flavine adenine dinucleotide (FAD), and an 80 kDa domain containing a molybdenum cofactor (MoCo) in which a substrate binding site is located. 1)AO catalyzes the oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. The representative N-heterocyclic-containing drugs that serve as substrates for AO are famciclovir, methotrexate, 6-mercaptopurine, and cinchona alkaloids. [1][2][3][4][5][6] In addition, the atypical antipsychotic drug, ziprasidone, is mainly metabolized by AO-catalyzed reductive ring cleavage in human. 7,8) AO has several pharmacokinetically interesting properties of remarkable species differences, large strain differences in rat, and individual differences in some kinds of rat strains. Among those phenomena, species differences have been widely demonstrated in the metabolism of many drugs catalyzed by AO. They include an ocular hypotensive agent, brimonidine, 9) antiviral drugs, famciclovir and 6-deoxypenciclovir, 10) an antineoplastic drug, methotrexate, 11) an ultrashort acting hypnotic, zaleplon, 12) and an oral antitumor agent, zebularine.13) Thus, it is now well established that the variations in AO activity may be dependent on not only animal species, but also on the chemical structure of the substrate. Roughly speaking, AO activity is high in monkeys and humans, moderate to low in rats and mice, and deficient in dogs. Similar to those reports, we observed remarkable species differences, rat strain differences, and polymorphism-based individual differences in Donryu strain rat in the AO-catalyzed 2-oxidation activity of the (S)-enantiomer of RS-8359,14-18) The compound is a reversible and selective monoamine oxidase (MAO)-A inhibitor 19,20) and has been developed as an anti-depressant. 21,22) As to species differences, monkeys showed the highest activity followed by humans. Furthermore, monkey and human liver cytosol preparations exhibited a biphasic pattern in the Eadie-Hofstee plots for the 2-oxidation activity of (S)-RS-8359, but not rat and mouse liver cytosols. The expression system of monkey AO full cDNA suggested that the biphasic Eadie-Hofstee profile might be produced by the existence of two active sites in a single AO enzyme rather than by the existence of two AO isoforms. 23)Molecular cloning of AO cDNA has been accomplished in mouse, 24,25) rat, 26) rabbit, 27) bovine, 28) and human. 29-31) The deduced primary structure of AO proteins have been characterized with regard to consensus sequences for two distinct 2Fe-2S clusters and five MoCo-binding sites. Wright et al. 26) indicated that the kinetic differences of AO activity between male and female rats are due...

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confidence: 75%

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

Itoh

Asakawa

Hoshino

et al. 2009

Biological & Pharmaceutical Bulletin

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“…18,19) The main metabolic pathway of the compound is the AO-catalyzed 2-oxidation on the pyrimidine ring of the molecule. Similar to many reports on AO, we observed a remarkable species differences, [20][21][22] a large strain difference in rat, 23) and an individual difference in Donryu strain rat 24) in the 2-oxidation activity. Further, we reported that a minor 130 kDa subunit in addition to a 150 kDa subunit was observed in the sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE)/Western blot analysis of monkey and human AO but not in rat AO.…”

Section: )supporting

confidence: 76%

Properties of 130 kDa Subunit of Monkey Aldehyde Oxidase

Asakawa

Itoh

Adachi

et al. 2008

Biological & Pharmaceutical Bulletin

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Aldehyde oxidase (AO, EC 1.2.3.1) is a major member of the molybdenum hydroxylase family along with xanthine oxidase. Both enzymes consist of a homodimer with a subunit molecular mass of about 150 kDa. Each subunit contains a molybdopterin cofactor, a flavin-adenine dinucleotide (FAD), and two different 2Fe-2S redox centers that are essential for catalytic activity. AO catalyzes the oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. Representative N-heterocyclic-containing drugs that serve as substrates for AO are famciclovir, methotrexate, 6-mercaptopurine, and cinchona alkaloids. [1][2][3][4][5][6] The oxidation mode by cytosolic AO is a nucleophilic attack at an electron-deficient carbon, which is different from an electrophilic attack at an electron-rich carbon by microsomal cytochrome P450, indicating that AO has complementary substrate specificities with P450 in the metabolism of xenobiotics. In addition, AO can catalyze in vitro reduction of a variety of functional groups including sulfoxides, N-oxides, azo dyes, and N-hydroxycarbamoyl substituents in the presence of an appropriate electron donor. 6) In fact, the atypical antipsychotic drug, ziprasidone, is mostly metabolized to its reductive ring-cleaved S-methyldihydroziprasidone by AO in human. 7,8) One of characteristics of AO is a marked species difference. For example, Sugihara et al. 9) investigated the enzyme activity in several animal species using a few model substrates with relatively simple chemical structures. Extremely high benzaldehyde oxidase activity was observed in monkey and low activity in guinea pig. 2-Hydroxypyrimidine was oxidized at the highest rate in rabbit and rat and at a low rate in mouse. Monkey showed the highest phthalazine oxidase activity among the animal species studied. N 1 -methylnicotinamide oxidase activity was highest in rabbit and low in rat and mouse. Preliminary experiments demonstrated that human AO shows similar substrate specificity to that of monkey. Further, many medicines have been reported to show significant species differences in AO-catalyzed metabolism. They include an ocular hypotensive agent, brimonidine, 10) an antiviral drug, famciclovir and 6-deoxypenciclovir, 11) an antineoplastic drug, methotrexate, 12,13) an ultra-short acting hypnotic, zaleplon, 14) and an oral antitumor agent, zebularine. 15)Thus, it is now well established that the variations of AO activity may be dependent on not only animal species, but also on the chemical structures of the substrate. Roughly speaking, AO activity is high in monkey and human, moderate to low in rat and mouse, and deficient in dog. We have been studying the metabolism of RS-8359, [(Ϯ)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta-[d]-pyrimidine], which is a reversible and selective monoamine oxidase A (MAO-A) inhibitor 16,17) and has been developed as an anti-depressant. 18,19) The main metabolic pathway of the compound is the AO-catalyzed 2-oxidation on the pyrimidine ring of the molecule. Simi...

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“…Thus, the more polar and positive charged residues seem to affect the surface charge of the protein, which results in higher stability of hAOX1. This also might influence its interaction with other proteins and/or posttranslational modifications of the protein, as suggested by Itoh et al (2007c) in a report on the characterization of SNPs in Donryu rats.…”

Section: Hartmann Et Almentioning

confidence: 99%

“…A change in the monomer/dimer ratio has been reported previously in AO and XDH enzymes with similar variants in proximity to the FeS clusters. In SNPs identified in Donryu rats, the amino acid exchange G101S in proximity to FeSII also resulted in the production of the monomeric form of AOX1 (Itoh et al, 2007c). In addition, in a human patient suffering from xanthinuria I, a mutation resulting in the amino acid exchange R149C was identified in the XDH gene (Sakamoto et al, 2001).…”

Section: Characterization Of Single Nucleotide Polymorphisms Of Haox1mentioning

confidence: 99%

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

et al. 2012

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ABSTRACT:Aldehyde oxidase (AO) is a complex molybdo-flavoprotein that belongs to the xanthine oxidase family. AO is active as a homodimer, and each 150-kDa monomer binds two distinct [2Fe2S] clusters, FAD, and the molybdenum cofactor. AO has an important role in the metabolism of drugs based on its broad substrate specificity oxidizing aromatic aza-heterocycles, for example, was obtained with a purity of 95% and a yield of 50 g/l E. coli culture. Site-directed mutagenesis of the hAOX1 cDNA allowed the purification of protein variants bearing the amino acid changes R802C, R921H, N1135S, and H1297R, which correspond to some of the identified SNPs. The hAOX1 variants were purified and compared with the wild-type protein relative to activity, oligomerization state, and metal content. Our data show that the mutation of each amino acid residue has a variable impact on the ability of hAOX1 to metabolize selected substrates. Thus, the human population is characterized by the presence of functionally inactive hAOX1 allelic variants as well as variants encoding enzymes with different catalytic activities. Our results indicate that the presence of these allelic variants should be considered for the design of future drugs.

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Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

Cited by 21 publications

References 22 publications

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

Properties of 130 kDa Subunit of Monkey Aldehyde Oxidase

The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

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