Effects of Selenium Deficiency on Aldehyde Oxidase 1 in Rats

Abstract

Aldehyde oxidase 1 (AOX1, EC 1.2.3.1) and xanthine oxidase are major members of the molybdo-flavoenzyme family. Both enzymes consist of a homodimer with a subunit molecular mass of about 150 kDa. AOX1 catalyzes the oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. [1][2][3] The representative N-heterocyclic-containing drugs that serve as substrates for AOX1 are famciclovir, 4) methotrexate, 5) 6-mercaptopurine, 6) and cinchona alkaloids. 7) In addition, the atypical antipsychotic drug, ziprasidone, is mainly metabolized by AOX1-catalyzed reductive ring cleavage in human. 8) Retinal is an aldehyde derivative of vitamin A that is oxidized to transcriptional retinoic acid by retinal oxidase. Retinal oxidase was found to be identical to AOX1. 9) Although retinal can be considered to be a physiological substrate of AOX1, the possibility was doubted by Garattini et al. in mouse liver cytosolic extracts due to higher activity of aldehyde dehydrogenase than that of the combined activities of AOX1 and aldehyde oxidase homologue 1 (AOH1).3) AOX1 might have an indirect role in biogenic neurotransmitter amine metabolism via biotransformation of their oxidatively deaminated intermediate aldehydes to carboxylic acids. 10) Thus, AOX1 is definitely a kind of drug-metabolizing enzyme, but its physiological role has not yet been revealed. AOX1 has some interesting pharmacokinetic properties. It is well known that there are remarkable species differences in AOX1 activity depending on not only animal species but also on the chemical structure of the substrate. Roughly speaking, AOX1 activity is high in monkey and human, moderate to low in rat and mouse, and deficient in dog.1,2) Large strain differences in rat, and individual differences in some kinds of rat strains have also been reported. [11][12][13][14][15] We demonstrated that an obvious individual difference in AOX1 activity in Donryu strain rats is derived from a single nucleotide substitution of the AOX1 gene consisting of approximately 4300 base pairs. In addition, the mechanism of the individual difference is true to strain differences in rat. 16,17) Many drug metabolizing enzymes are generally susceptible to change caused by a variety of internal and external factors. Genetic mutation is one of major internal factors as well as are disease status and age. Nutritional condition is given as an example of an external factor along with enzyme induction and inhibition, which are often caused by concurrently administered medicines, herbs, and foods. As for AOX1, the induction by dioxine 18) and the in vitro inhibition by a number of medicines such as raloxifen and ethinylestradiol 19) have been reported. Furthermore, the amount of retinal oxidase, namely AOX1, has been demonstrated to be increased by zinc deficiency. 20,21) Selenium is an essential trace element similar to zinc. Selenium deficiency has been known to affect drug metabolizing enzymes differently: a severe decrease of Se-dependent glutathione peroxidase (GSH-Px...

Selenium-Enriched Fatty Goose Liver Attenuates Alcohol-Induced Liver Injury in Mice by Enhancing Antioxidant Capability

“…SOD, GSH-Px, and GSH play important roles during the process by scavenging reactive oxygen species or by preventing their formation (Kabuto et al, 2003). GSH-Px is Se dependent and the deficiency of Se can lead to significantly reduced GSH-Px activity in rats (Itoh et al, 2009;Markiewicz-Górka et al, 2011). This relationship was also observed in this research.…”

Nimesulide increases the aldehyde oxidase activity of humans and rats

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Assay of labile estrogen o-quinones, potent carcinogenic molecular species, by high performance liquid chromatography–electrospray ionization tandem mass spectrometry with phenazine derivatization

“…Freshly prepared solutions of catechol estrogens were used for each experiment. Rat liver microsomal fraction (Four weeks old, male, Wistar strain, 20 mg protein/ml) used in this study was prepared [21] and donated by Dr. Yorihisa Tanaka (Department of Drug Metabolism and Pharmacokinetics, Tohoku Pharmaceutical University).…”