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Research ArticleArticle

Lack of Formation of Aldehyde Oxidase Dimer Possibly Due to 377G>A Nucleotide Substitution

Kunio Itoh, Hiroaki Maruyama, Mayuko Adachi, Kouichi Hoshino, Nobuaki Watanabe and Yorihisa Tanaka
Drug Metabolism and Disposition October 2007, 35 (10) 1860-1864; DOI: https://doi.org/10.1124/dmd.107.015503
Kunio Itoh
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Hiroaki Maruyama
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Mayuko Adachi
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Kouichi Hoshino
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Nobuaki Watanabe
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Yorihisa Tanaka
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Abstract

In addition to the many articles reporting on the marked differences in species and large differences in rat strains in response to aldehyde oxidase (AO), individual differences in some rat strains have also been reported. However, little has been clarified about any related molecular biological mechanisms. We previously revealed that nucleotide substitutions of 377G>A and 2604C>T in the AO gene might be responsible for individual differences in AO activity in Donryu strain rats. By using native polyacrylamide gel electrophoresis/Western blotting in this study, the lack of formation of the AO dimer protein, which is essential for catalytic activity, was shown in poor metabolizer Donryu rats, and this could be a major reason for the individual differences. Rat strain differences were also verified from the same perspectives of nucleotide substitutions and expression levels of a dimer protein. Rat strains with high AO activity showed nucleotide sequences of (377G, 2604C) and a dimer protein. In the case of those with low AO activity, the nucleotide at position 2604 was fixed at T, but varied at position 377, such as G, G/A, and A. An AO dimer was detected in the liver cytosols of rat strains with (377G, 2604T), whereas a monomer was observed in those with (377A, 2604T). These results suggest that the lack of formation of a dimer protein leading to loss of catalytic activity might be due to 377G>A nucleotide substitution. Individual and strain differences in AO activity in rats could be explained by this 377G>A substitution, at least in the rat strains used in this study.

Footnotes

  • doi:10.1124/dmd.107.015503.

  • ABBREVIATIONS: AO, aldehyde oxidase; SD, Sprague-Dawley; RS-8359, (±)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine; MAO-A, monoamine oxidase A; PM, poor metabolizer; EM, extensive metabolizer; UM, ultrarapid metabolizer; PCR, polymerase chain reaction; native PAGE, native polyacrylamide gel electrophoresis; HPLC, high-performance liquid chromatography; PVDF, polyvinylidene difluoride.

    • Received March 1, 2007.
    • Accepted July 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (10)
Drug Metabolism and Disposition
Vol. 35, Issue 10
1 Oct 2007
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Research ArticleArticle

Lack of Formation of Aldehyde Oxidase Dimer Possibly Due to 377G>A Nucleotide Substitution

Kunio Itoh, Hiroaki Maruyama, Mayuko Adachi, Kouichi Hoshino, Nobuaki Watanabe and Yorihisa Tanaka
Drug Metabolism and Disposition October 1, 2007, 35 (10) 1860-1864; DOI: https://doi.org/10.1124/dmd.107.015503

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Research ArticleArticle

Lack of Formation of Aldehyde Oxidase Dimer Possibly Due to 377G>A Nucleotide Substitution

Kunio Itoh, Hiroaki Maruyama, Mayuko Adachi, Kouichi Hoshino, Nobuaki Watanabe and Yorihisa Tanaka
Drug Metabolism and Disposition October 1, 2007, 35 (10) 1860-1864; DOI: https://doi.org/10.1124/dmd.107.015503
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