Effect of Tea Beverages on Aldehyde Oxidase Activity

doi:10.2133/dmpk.DMPK-10-NT-078

Drug Metabolism and Pharmacokinetics

Volume 26, Issue 1, 2011, Pages 94-101

https://doi.org/10.2133/dmpk.DMPK-10-NT-078 Get rights and content

Summary:

Aldehyde oxidase (AO) plays an important role in metabolizing antitumor and antiviral drugs, including methotrexate, cyclophosphamide and acyclovir. Green tea and its catechins have been shown to modulate the activities of various xenobiotic-metabolizing cytochrome P450 species, both in vivo and in vitro, but their effect on AO has not been studied. Therefore, we evaluated the effect of tea beverages on AO activity in rat and human liver cytosol. We also investigated the influence of several catechins on AO activity in rat liver cytosol. AO activity was evaluated in terms of oxidation of N-1-methylnicotinamide to N1-methyl-2-pyridone-5-carboxamide and N-1-methyl-4-pyridone-3-carboxamide. Bottled green tea beverages at 10% (vol/vol) inhibited AO activity by 90.0-93.5%, while at 1.0% (vol/vol), they reduced AO activity by 73.9-90.0%. At 0.1% (vol/vol), green tea II and III, which have high contents of catechins and their derivatives, inhibited AO activity by 24.3% and 38.8%, respectively. Bottled mineral water had no effect. AO activity was inhibited potently by epicatechin and epicatechin gallate. These results indicate that the AO-inhibitory activity of tea beverages is predominantly due to catechins and their derivatives. Thus, consumption of tea beverages may cause a decrease of AO activity, which may result in reduced clearance of drugs that are AO substrates.

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Raloxifene was the most potent drug that showed a half-maximal inhibitory concentration (IC50) of 2.9 nM (Obach, Huynh, Allen, & Beedham, 2004). Compounds from natural products, such as catechin derivatives, flavonoids, and stilbenoids also show a comparable inhibitory effect on AOX at low micromolar concentrations (Barr, Jones, Oberlies, & Paine, 2015; Hamzeh-Mivehroud, Rahmani, Rashidi, Hosseinpour Feizi, & Dastmalchi, 2013; Tayama et al., 2011). Some of these inhibitors with micromolar potency also have a potency comparable to CYP450s at the same concentration (Nirogi et al., 2014).
Oxidative metabolism is one of the major biotransformation reactions that regulates the exposure of xenobiotics and their metabolites in the circulatory system and local tissues and organs, and influences their efficacy and toxicity. Although cytochrome (CY)P450s play critical roles in the oxidative reaction, extensive CYP450-independent oxidative metabolism also occurs in some xenobiotics, such as aldehyde oxidase, xanthine oxidoreductase, flavin-containing monooxygenase, monoamine oxidase, alcohol dehydrogenase, or aldehyde dehydrogenase-dependent oxidative metabolism. Drugs form a large portion of xenobiotics and are the primary target of this review. The common reaction mechanisms and roles of non-CYP450 enzymes in metabolism, factors affecting the expression and activity of non-CYP450 enzymes in terms of inhibition, induction, regulation, and species differences in pharmaceutical research and development have been summarized. These non-CYP450 enzymes are detoxifying enzymes, although sometimes they mediate severe toxicity. Synthetic or natural chemicals serve as inhibitors for these non-CYP450 enzymes. However, pharmacokinetic-based drug interactions through these inhibitors have rarely been reported in vivo. Although multiple mechanisms participate in the basal expression and regulation of non-CYP450 enzymes, only a limited number of inducers upregulate their expression. Therefore, these enzymes are considered non-inducible or less inducible. Overall, this review focuses on the potential xenobiotic factors that contribute to variations in gene expression levels and the activities of non-CYP450 enzymes.
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Furthermore, hydralazine has been shown to be an inhibitor of AOX activity in rabbit, guinea pig, baboon, and human liver [17–19]. In addition to drugs, diet-derived constituents were also reported to inhibit AOX activity (e.g., epicatechin gallate and epigallocatechin gallate) [20,21]. In this context, an interesting compound is represented by norharmane, which exhibits an isoform-specific inhibitory effect on AOX3 in mouse liver [13].
As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug–drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC₅₀ values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O⁶-benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC₅₀ values. We also evaluated the potential DDI between an AOX substrate (O⁶-benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC_0–24) of O⁶-benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context.
Xanthine Oxidoreductase and Aldehyde Oxidases
2018, Comprehensive Toxicology: Third Edition
Aldehyde oxidases (AOXs) and xanthine oxidoreductase (XOR) are closely related enzymes with very similar primary structures comprising two identical subunits each of which contains four redox centers: one molybdopterin cofactor, one flavin adenine dinucleotide (oxidized form) molecule, and two iron–sulfur clusters. The enzymes, also referred to as molybdenum hydroxylases, catalyze both oxidation and reduction reactions and play a significant role in the metabolism of drugs and endobiotics including endogenous purines. Generally, oxidation reactions involve nucleophilic attack via a Mo–OH ligand at a carbon atom in N-heterocycles and aldehydes with electrons transferred ultimately to molecular oxygen or NAD⁺ (nicotinamide adenine dinucleotide—the oxidized form). Reduction of oxygen can generate reactive oxygen species, which have been implicated in a variety of protective and pathophysiological functions. AOXs and XOR are widely distributed throughout the animal kingdom and probably originated from a single ancestor gene coding for a dehydrogenase form of XOR. While a single mammalian XOR is known, various mammalian AOX isoenzymes have been identified. The complement of active mammalian AOX genes varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3, and AOX4). In humans, the AOX1 and XOR genes are found on different arms of chromosome 2 and are both subject to complex regulation, the precise details of which have not yet been fully characterized. The 3D structures of bovine milk XOR, human AOX1, and mouse AOX3 are available and have provided valuable information on the catalytic mechanism of molybdenum hydroxylases. This chapter provides an overview of the current knowledge on the structure, evolution, and function of these highly complex enzymes.
Effect of Bakumondo-to on cytochrome P450 activities in rat liver microsomes
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St John’s wort (Hypericum perforatum), an herbal antidepressant, is also well-known as a potent inducer of cytochrome P450 (CYP) 3A (Roby et al., 2000; Wang et al., 2001). In addition, analogs of catechin are inhibitors of CYPs, xanthine oxidase, and aldehyde oxidase (Tayama et al., 2011). Shoseiryuto, another traditional herbal medication, demonstrated CYP3A inhibitory activity in rat liver microsomes (Makino et al., 2006).
Bakumondo-to is a traditional herbal medicine. It has been widely used for the treatment of chronic airway diseases. Recently, it was reported that several herbal medicines affected cytochrome P450 (CYP). However, there is little information about the effects of Bakumondo-to on CYP activities. In this study, we evaluated the effects of Bakumondo-to on CYP activities in rat liver microsomes. Rats were orally treated twice a day with Bakumondo-to at doses of 2.0 g/kg body weight/day for 4 days. CYP activities were determined in liver microsomes isolated from treated rats. CYP1A2, CYP2C, and CYP3A activities were measured using their specific substrates [7-methoxyresorufin, 7-methoxy-4-(trifluoromethyl)-coumarin, and 7-benzyloxyquinoline, respectively]. Bakumondo-to decreased CYP1A2 activity by 42.5 ± 7.8%, increased CYP2C activity by 158.0 ± 29.6%, and decreased CYP3A activity to 81.5 ± 7.8% of the control level. Activities were expressed as percentages of the control.
Bakumondo-to induced CYP2C activity and decreased CYP1A2 activity; it may cause drug-herbal interactions. It is suggested that combinations of Bakumondo-to and drugs that are metabolized by CYP1A2 and CYP2C should be carefully used in clinical settings.
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Citation Excerpt :
Furthermore, 6-deoxypenciclovir and zoniporide show substrate inhibition at high concentrations, allowing the prediction of PK in humans [85]. Constituents of green tea, oolong tea, and blended tea have been shown to inhibit aldehyde oxidase activity [86], with concentration-dependent decreases in NMN metabolism. Contents of tea include caffeine (103.1 mg/L), epigallocatechin gallate (196.0 mg/L), epigallocatechin (78.1 mg/L), gallocatechin gallate (70.5 mg/L), epicatechin (28.5 mg/L), catechin (25.6 mg/L), and epicatechin gallate (19.6 mg/L), and among these catechin, epigallocatechin, epicatechin, and epicatechin gallate are potential inhibitors of aldehyde oxidase [86].
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The polyphenolic structure allows electron delocalization, conferring high reactivity to quench free radicals [37]. Tea catechins eliminate reactive oxygen and nitric radicals, and also act as chelators of metal ions active in the redox system [38,39]. The antioxidant action of GTE may also explain the hypotensive and cardioprotective action of GTE.
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NoteEffect of Tea Beverages on Aldehyde Oxidase Activity

Summary:

Comp. Biochem. Physiol., B

Drug Metab. Pharmacokinet.

Drug Metab. Pharmacokinet.

Biochem. Biophys. Res. Commun.

Prev. Med.

Food Chem. Toxicol.

J. Biol. Chem.

J. Chromatogr.

J. Biol. Chem.

Drug Metab. Pharmacokinet.

Prog. Med. Chem.

J. Biol. Chem.

J. Biol. Chem.

Differential inhibition of electron transfer to various electron acceptors. J. Biol. Chem.

III. The substrate-binding site. J. Biol. Chem.

Biochem. Pharmacol.

Molybdenum hydroxylases as drug metabolizing enzyme

Drug Metab. Rev.

Analysis of aldehyde oxidase and xanthine dehydrogenase/oxidase as possible candidate genes for autosomal recessive familial amyotrophic lateral sclerosis

Somat. Cell Mol. Genet.

Distribution and pathophysiologic role of molybdenum-containing enzymes

Histol. Histopathol.

Identification of the candidate ALS2 gene at chromosome 2q33 as a human aldehyde oxidase gene

Redox Rep.

Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide

Drug Metab. Dispos.

Molecular Neurobiology of Mammalian Brain

Bacteriological variations in a medio-mineral water bottled in polyethylene terephthalate containers

Ann. Ig.

Note
Effect of Tea Beverages on Aldehyde Oxidase Activity