Received for publication March 12, 2007.
Revised July 11, 2007.
Accepted for publication July 12, 2007.

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

Abstract

In addition to many papers on marked differences in species and large differences in rat strains in aldehyde oxidase (AO), individual differences in some rat strains have 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 of AO in Donryu strain rats. By using native-PAGE/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 (PM) 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 cases 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 lack of the formation of a dimer protein leading to loss of catalytic activity might be due to 377G>A nucleotide substitution. Individual and strain differences of AO in rats could be explained by this 377G>A substitution, at least in the rat strains used in this study.

Key words: pharmacogenetics, polymorphisms