Biol. Pharm. Bull. 30(7) 1191—1198 (2007)

lic fraction, is a major member of the molybdenum hydroxylase family along with xanthine oxidase. AO plays an important role in the oxidation of endogenous and exogenous Nheterocyclic compounds as well as aliphatic and aromatic aldehydes. A typical endogenous substrate for AO is retinal, which is transformed to biologically active retinoic acid. In contrast to an electrophilic attack by microsomal cytochrome P450, AO-catalyzed oxidation involves a nucleophilic attack on an electro-deficient carbon. This suggests that, in most cases, AO has complementary substrate specificities with cytochrome P450 in the metabolism of xenobiotics. Further, AO can also catalyze the reduction of several kinds of functional groups including sulfoxides, N-oxides, azo dyes, and N-hydroxycarbamoyl substituents. In fact, the atypical antipsychotic drug ziprasidone is a good example of a substance in humans that AO metabolizes to reductive ring-cleaved S-methyldihydroziprasidone. Marked species differences have been well documented for the AO-catalyzed metabolism of a wide range of N-heterocyclic drugs. They include carbazeran, brimonidine, zaleplon, methotrexate, and famciclovir. In addition, large rat strain differences in AO have been reported for benzaldehyde and methotrexate, and even the existence of striking variations in AO activity has been noted in Sprague–Dawley rats and Wistar rats. We also observed phenomena related to species differences, rat strain differences, and rat individual differences in the metabolism of RS-8359, which is a selective and reversible MAO-A inhibitor and has been developed as an antidepressant. AO is a homodimer with a subunit molecular mass of approximately 150 kDa. Each monomeric subunit contains a molybdopterin cofactor, a FAD, and two different 2Fe– 2S redox centers. The molecular cloning of AO cDNA has been achieved in mouse, rat, rabbit, bovine, and human. The deduced primary structure of AO proteins has been characterized with regard to consensus sequences for two distinct 2Fe–2S clusters and five molybdopterin-binding sites. Wright et al. indicated that the kinetic differences of AO activity between male and female rats are due to sensitivity to redox manipulation of AO, which is most likely expressed by a single AO gene. In human and mouse, the structures of the 5 -flanking region containing several putative regulatory elements were determined. In spite of the rapid progress in the molecular biology of AO, many published papers still seem to be limited to only the phenomena themselves. Little is known about the molecular mechanism of such pharmacokinetically and pharmacologically important drug-metabolism events as species differences, strain differences, and individual variations. In this study, we investigated the properties of expressed and liver aldehyde oxidase of male cynomolgus monkeys as one of the topics related to the mechanism of species differences requiring clarification.