Interrogating the Inhibition Mechanisms of Human Aldehyde Oxidase by X-ray Crystallography and NMR Spectroscopy: The Raloxifene Case

Mota, Cristiano; Diniz, Ana; Coelho, Catarina; Santos‐Silva, Teresa; Esmaeeli, Mariam; Leimkühler, Silke; Cabrita, Eurico J.; Marcelo, Filipa; Romão, Maria João

doi:10.1021/acs.jmedchem.1c01125

Cited by 5 publications

(1 citation statement)

References 35 publications

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“…Raloxifene is a potent AO inhibitor, which reportedly inhibits AO via both a competitive and uncompetitive mechanism that is not time-dependent (Obach, 2004;Barr and Jones, 2013;Foti et al, 2016;Mota et al, 2021). As expected, the presence of GSH had no influence on the inhibitory activity of raloxifene.…”

Section: Discussionsupporting

confidence: 64%

Mechanistic Investigation of the Time-Dependent Aldehyde Oxidase Inhibitor Hydralazine

et al. 2023

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The anti-hypertensive agent hydralazine is a time-dependent inhibitor of the cytosolic drug metabolizing enzyme aldehyde oxidase (AO). Glutathione (GSH) was found to suppress the inhibition of AO by hydralazine in multiple enzyme sources (human liver and kidney cytosol, human liver S9, rat liver S9, and recombinant human AO) and with different AO substrates (zoniporide, O 6 -benzylguanine, and dantrolene). Hydralazine-induced AO inactivation was unaffected when GSH was added to the incubation mixture after pre-incubation of hydralazine with AO (rather than during the pre-incubation), suggesting that GSH traps a hydralazine reactive intermediate prior to enzyme inactivation. Consistent with previous reports of 1phthalazylmercapturic acid formation when hydralazine was incubated with N-acetylcysteine, we detected a metabolite producing an MS/MS spectrum consistent with a 1-phthalazyl-GSH conjugate. O 6 -Benzylguanine, an AO substrate, did not protect against hydralazine-induced AO inactivation, implying that hydralazine does not compete with O 6 -benzylguanine for binding to the AO active site. Catalase also failed to protect AO from hydralazine-induced inactivation, suggesting that hydrogen peroxide is not involved. However, an allosteric AO inhibitor (thioridazine) offered some protection, indicating a catalytic role for AO in the bioactivation of hydralazine. AO inhibition by phthalazine (a substrate and inhibitor of AO and a metabolite of hydralazine) was unaffected by the presence of GSH. GSH also prevented hydralazine from inhibiting the nitro-reduction of dantrolene by AO. Furthermore, the GSH-hydralazine combination stimulated dantrolene reduction. Phthalazine inhibited only oxidation reactions, not reduction of dantrolene. Together these results support the hypothesis that hydralazine is converted to a reactive intermediate that inactivates AO.

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Section: Discussionsupporting

confidence: 64%

Mechanistic Investigation of the Time-Dependent Aldehyde Oxidase Inhibitor Hydralazine

et al. 2023

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Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

Rendić¹,

Crouch

Guengerich

2022

Arch Toxicol

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This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, “general chemicals,” natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10–15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.

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Occurrence, analysis and removal of pesticides, hormones, pharmaceuticals, and other contaminants in soil and water streams for the past two decades: a review

Kanan

Moyet²,

Obeideen³

et al. 2022

Res Chem Intermed

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Interrogating the Inhibition Mechanisms of Human Aldehyde Oxidase by X-ray Crystallography and NMR Spectroscopy: The Raloxifene Case

Cited by 5 publications

References 35 publications

Mechanistic Investigation of the Time-Dependent Aldehyde Oxidase Inhibitor Hydralazine

Mechanistic Investigation of the Time-Dependent Aldehyde Oxidase Inhibitor Hydralazine

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

Occurrence, analysis and removal of pesticides, hormones, pharmaceuticals, and other contaminants in soil and water streams for the past two decades: a review

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