Advances in the study of aldehyde oxidases / 药学学报

Aldehyde oxidase (AOX), a highly conserved molybdoflavoenzyme in mammal cytoplasm, has broad substrate specificity and ability to catalyze the oxidation of aldehydes and nitrogen, oxygen-containing heterocyclic rings. AOX was found to widely distribute with the individual differences in vivo and plays an important role in phase I metabolism of drugs and xenobiotics. The biological characteristics of AOX and its contributions in drug metabolism are introduced briefly in this review.

Molybdenum hydroxylase super family shows circadian activity fluctuation in mice liver: emphasis on aldehyde hydroxylase and xanthine oxidase

Non-CYP oxidase enzymes are important system in biotransformation of drugs and environmental pollutants. Molybdenum containing oxidase enzymes such as aldehyde oxidase and xanthine oxidase are constitutive tissue enzymes that metabolize several drug moieties. Herein, we evaluated the circadian rhythm of these two enzymes in mice liver using different substrate/oxygen donor couples. Aldehyde oxidase showed typical rhythmic fluctuation with peak activity at night cycle and minimum activity at light cycle using pthalazine/ferricyanide and 3-methylisoquinoline/ferricyanide substrates. On the other hand, xanthine oxidase showed interrupted diurnal rhythm, however peak and minimum enzyme activities were similar to aldehyde oxidase circadian rhythm. In conclusion, diurnal rhythm of both molybdenum hydroxylase enzymes was confirmed and validated in mice liver tissue that might provide further insights in the experimental evaluation of phase-I pharmacokinetics for new drugs

Effects of Supplementation with a Schizandrin C Derivative DDB-mixed Preparation (DWP-04) on Antioxidant Activity in Cisplatin-induced Nephrotoxicity in Rats / 대한신장학회지

PURPOSE: This study investigated the effect of reducing cisplatin induced nephrotoxicity with DWP-04 that is the compound of Schizandrin C derivative biphenyldimethyl dicarboxylate (DDB), glutathione and selenium. For the purpose of observation is that how DWP-04 has influence on mechanism of reducing cisplatin induced nephrotoxicity with renal function test, free radical formation and detoxification enzyme system in renal tissue. METHODS: Five groups of rats were dosed with vehicle, cisplatin (2 mg/kg i.p.), cisplatin+DWP-04 (100, 200 mg/kg po), or cisplatin+sodium thiosulfate (200 mg/kg i.p.) daily for 4 weeks. RESULTS: Serum creatinine, lactate dehydrogenase and activity of hydroxy radical increased in the cisplatin group and suppressed in the cisplatin+DWP-04 group compared to the cisplatin group. The renal tissue concentration of lipid peroxidase and lipofuscin were increased in the cisplatin group compared to the other groups. The activity of aminopyrine N-demethylase, aniline hydroxylase, aldehyde oxidase and xanthine oxidase, of which free radical formation system in kidney was also decreased in the cisplatin+DWP-04 group compared to the cisplatin and cisplatin+sodium thiosulfate group. The activity of detoxification system of free radical, such as glutathione S-transferase, superoxide dismutase, catalase and glutathione peroxidase were markedly increased in the cisplatin+DWP-04 group than the cisplatin and the cisplatin+sodium thiosulfate group (p<0.05). CONCLUSION: It can be concluded that the mechanism of decreasing cisplatin-induced nephrotoxicity by DWP-04 is that the decreasing of the amount of lipid peroxide and lipofuscin in the renal tissue by increasing activity of the antioxidant defense system and the decreasing of reactive oxygen species by increasing detoxification enzyme activity.

In vitro hepatic metabolism of cinchona antimalarials by hamster enzymes

Cinchona alkaloids [quinidine and cinchonine] were incubated with aldehyde oxidase and microsomal monooxygenases from hamster liver. Reversed-phase HPLC method was used to separate quinidine and cichonine from their metabolites. Characterisation of the metabolites arising from aldehyde oxidase by infrared and mass spectral analysis, exhibited that quinidine and cinchonine were oxidised to the corresponding 2'-quinolones. In vitro microsomal metabolites of quinidine were identified as 2'-quinidinone and O-desmethylquinidine. Incubation of cinchonine with microsomal enzymes showed that no metabolites were generated

Current and new strategies in therapy of neurodegenerative disorders: amyotrophic lateral sclerosis as a model

For years researchers have known that free radicals can cause cell degeneration, especially in the brain, so there is a role for the oxidative stress and free radicals in the chronic neurodegenerative disorders. Riluzole is recommended for improving the prognosis of patients suffering from the neurodegenerative disorder, Amyotrophic lateral sclerosis [ALS], and it thought to be acting as nueroprotective agent by the inhibition of glutamatergic transmission in the CNS. The familial [ALS], has been mapped to chromosome 2q33 and aldehyde oxidise enzyme has been mapped also with the same gene 2q33. So it noteworthy to make a link between Riluzol and aldehyde oxidase and the possible interaction between them in the CNS, which may contribute to the neuroprotective effect of Riluzole by inhibiting ROS production or altering the balance between hydrogen peroxide [H[2]O[2]] and superoxide anion [O[2]]

Role of molybdenum hydroxylases in diseases

The role of molybdenum-containing enzymes, aldehyde oxidase and xanthine oxidase in the production of reactive oxygen species has been discussed in term of mechanism of action. Unlike cytochrome P450 and other monooxygenase systems, the molybdenum hydroxylases carry out their reactions using water rather than molecular oxygen as the source of the oxygen atom incorporated into the product, and generated rather than consumed electrons. Aldehyde oxidase and xanthine oxidase differ in their substrates and inhibitor specificity. While aldehyde oxidase is a predominant oxidase, xanthine oxidase can undergo inter-conversion between oxidase/ dehydrogenase forms under pathological conditions such as ischaemia. Nevertheless, the wide range of drugs, xenobiotics and endogenous chemicals that interact with these enzymes, particularly aldehyde oxidase, highlight the importance of these enzymes in drug oxidation, detoxification and activation. Aldehyde oxidase and xanthine oxidase have been linked to some diseases such as neurodegenerative and ischaemic disorders, respectively. In vivo, oxidation of aldehyde oxidase-substrates such as ethanol-derived acetaldehyde, retinal and NADH may alter the balance of ROS production by this enzyme leading to neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease and schizophrenia. In addition, aldehyde oxidase has been implicated in pathophysiology of alcohol liver injury, visual processes, synthesis of retinoic acid and reperfusion tissue injury. Under pathological conditions, such as ischaemia-reperfusion injury, both enzymes may participate

Metabolism of 5-aminoquinoline with liver cytosol enzyme.

In vitro oxidation and acetylation of 5-aminoquinoline by rabbit liver enzyme preparation has been investigated. Incubation of 5-aminoquinoline with cytosol fraction of the enzyme preparation in the presence of acetyl coenzyme-A gave rise to three different products, viz. 5-amino-2-hydroxy quinoline, 5-acetyl-aminoquinoline and 5-acetylamino-2-hydroxy quinoline due to the combined action of aldehyde oxidase and N-acetyl transferase. The metabolites thus obtained by enzyme catalysed reactions were isolated and separated by TLC, HPLC and subsequently characterised by IR and mass spectral fragmentation techniques.

Isoenzyme analyses of Malaysian Schistosoma, S. mekongi and S. japonicum by isoelectric focusing in polyacrylamide gel.

Isoenzyme patterns of adult Malaysian Schistosoma, S. mekongi and S. japonicum strains were analysed by isoelectric focusing (IEF) in polyacrylamide gel. Enzyme patterns obtained from Malaysian Schistosoma homogenates differed from those of S. mekongi and S. japonicum strains. Malaysian Schistosoma was found to differ from S. japonicum by 8 enzymes, namely phosphoglucomutase, phosphoglucoisomerase, malate dehydrogenase, acid phosphatase, hydroxy-butyrate dehydrogenase, hexokinase and alkaline phosphatase, and from S. mekongi by phosphoglucomutase, malate dehydrogenase, aldolase and alkaline phosphatase. These results and the distinct biology of the parasite suggest that Malaysian Schistosoma is a new species in the S. japonicum complex.