title: Lack of formation of aldehyde oxidase dimer possibly due to 377G>A nucleotide substitution.
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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Tohoku Pharmaceutical University, Sendai, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Itoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Maruyama
authors.forename: Mayuko
authors.initials: M
authors.lastname: Adachi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hoshino
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Yorihisa
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D042931:Aldehyde Oxidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D003600:Cytosol / Q000201:enzymology; D019281:Dimerization; D008099:Liver / Q000201:enzymology*; D008297:Male; D009711:Nucleotides / Q000235:genetics; D011110:Polymorphism, Genetic; D051381:Rats; D011919:Rats, Inbred Strains; D017422:Sequence Analysis, DNA; D013045:Species Specificity
chemical_list: D009711:Nucleotides; D042931:Aldehyde Oxidase