Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Sasaki, Takuma; Masubuchi, Akiko; Yamamura, Manabu; Watanabe, Nobuaki; Hiratsuka, Masahiro; Mizugaki, Michinao; Itoh, Kunio; Tanaka, Yorihisa

doi:10.1002/bdd.504

Cited by 16 publications

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References 34 publications

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“…The genetic variation in aldehyde oxidase was also reported by the electrophoresis method (Kunieda et al, 1999). Similar to those reports, we observed remarkable species differences and rat strain differences in the metabolism of the (S)-enantiomer of RS-8359 Sasaki et al, 2006). During the study of rat strain differences in the 2-oxidation activity of RS-8359, we were aware of the individual variations in Donryu rats, as shown in Wistar rats (Gluecksohn-Waelsch et al, 1967) and Sprague-Dawley (SD) rats (Beedham, 1998).…”

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Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

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“…A recent study by Sasaki et al (2006) revealed the low 2-oxidation activity of the (S)-enantiomer in the SD strain. The amino acid sequences of aldehyde oxidase of female SD rats have 1332 of 1333 identities to those of the Donryu PM rats, and both have 110Ser and 852Val sequences.…”

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confidence: 99%

Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

et al. 2007

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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.…”

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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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“…15) In addition, large rat strain differences in AO have been reported for benzaldehyde 16) and methotrexate, 17) and even the existence of striking variations in AO activity has been noted in Sprague-Dawley rats 18) and Wistar rats. 19) We also observed phenomena related to species differences, 20,21) rat strain differences, 22) and rat individual differences 23) in the metabolism of RS-8359, which is a selective and reversible MAO-A inhibitor [24][25][26] and has been developed as an antidepressant. 27,28) AO is a homodimer with a subunit molecular mass of approximately 150 kDa.…”

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Cloning, Expression, and Characterization of Male Cynomolgus Monkey Liver Aldehyde Oxidase

Hoshino

Itoh

Masubuchi

et al. 2007

Biological & Pharmaceutical Bulletin

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In this study, we investigated the properties of monkey liver aldehyde oxidase directed toward the clarification of species differences. The aldehyde oxidase preparation purified from male cynomolgus monkey liver cytosol showed a major 150 kDa Coomassie brilliant blue (CBB)-stained band together with a minor 130 kDa band using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Both bands were identified as being aldehyde oxidase by a database search of the MS data obtained with nano-liquid chromatography, quardrupole time of flight, mass spectrometry (nano-LC Q/TOF MS). Based on the sequence coverage, the 130 kDa protein was presumed to be deficient in 20-30 kDa mass from the N-terminus. Full male cynomolgus monkey aldehyde oxidase cDNA was cloned and sequenced with the four degenerate primers designed by considering the peptide sequences containing the amino acids specific for monkey aldehyde oxidase. The deduced amino acid sequences had 96% amino acid identity with those of human enzyme. The aldehyde oxidase expressed in Escherichia coli also exhibited two immunoreactive bands on SDS-PAGE/Western blot analysis. Further, the biphasic pattern was observed for Eadie-Hofstee plots of the (S)-enantiospecific 2-oxidation activity of RS-8359 with the expressed and cytosolic monkey liver aldehyde oxidase. The results suggested that two forms of aldehyde oxidase in monkey were the expression products by a single gene. In contrast, the similarly expressed rat aldehyde oxidase showed only one immunoreactive protein and monophasic pattern. The biphasic phenomenon could be caused by the existence of two aldehyde oxidase isoforms or two active sites in a single enzyme or some other reasons. Further studies on the problems of the biphasic pattern and species differences in aldehyde oxidase are needed.

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Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Cited by 16 publications

References 34 publications

Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

Genetic Polymorphism of Aldehyde Oxidase in Donryu Rats

Properties of 130 kDa Subunit of Monkey Aldehyde Oxidase

Cloning, Expression, and Characterization of Male Cynomolgus Monkey Liver Aldehyde Oxidase

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