The enzyme “aldehyde oxidase” is an iminium oxidase. Reaction with nicotine Δ1′(5′) iminium ion

Brandänge, Svante; Lindblom, Lars

doi:10.1016/0006-291x(79)91977-6

Cited by 100 publications

(52 citation statements)

References 13 publications

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“…Nicotine is mainly metabolized in liver by cytochrome P450 2A6 (CYP2A6) [117][118][119][120][121]. The principal nicotine-metabolizing pathway of nicotine is 5 -hydroxylation to 5 -hydroxynicotine [122,123] which is further oxidized to cotinine immediately [124][125][126], another metabolic pathway is N-demethylation to nornicotine and formaldehyde [127][128][129]. A detailed understanding of the mechanism of CYP2A6-catalyzed nicotine metabolism could provide a valuable mechanistic base for rational design of novel smoking cessation drugs.…”

Section: Nicotine Oxidationmentioning

confidence: 99%

“…With this free energy barrier difference, the calculations predict product abundance that 5 -hydroxynicotine is preponderant over the N-(hydroxymethyl)nornicotine by roughly a factor of 18:1. Since the subsequent processes of 5 -hydroxylation and Nmethylhydroxylation are quite faster [124][125][126][127][128][129] than the hydroxylation reaction itself, we might expect this 18:1 ratio to be conserved and continue onward to the cotitine and nornicotine products in nicotine metabolism. The predicted preference of 5 -hydroxylation over N-methylhydroxylation is in agreement with the experimental observation that cotinine is the primary metabolite of nicotine [121,[131][132][133][134].…”

Section: Nicotine Oxidationmentioning

confidence: 99%

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Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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Section: Nicotine Oxidationmentioning

confidence: 99%

Section: Nicotine Oxidationmentioning

confidence: 99%

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Wang

Han

2012

Coordination Chemistry Reviews

132

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“…As its name implies, AOX is known for its ability to oxidize aldehydes to carboxylic acids. However, AOX is also involved in the oxidation of nitrogen-containing heterocyclic compounds, as well as iminium ion intermediates (Brandänge and Lindblom, 1979;Whittlesea and Gorrod, 1993).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

Barr

Jones

2011

Drug Metab Dispos

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ABSTRACT:During the course of our research efforts to understand the kinetics of human aldehyde oxidase as a xenobiotic-clearing enzyme, we investigated the effect of eight different inhibitors on the oxidation of the probe substrate phthalazine. Saturation kinetic parameters for phthalazine oxidation in human liver cytosol were found to be the following:Inhibitory potency of the inhibitors tested ranged from 0.1 to 5 M. Of the eight different inhibitor compounds tested, seven were observed to inhibit through a mixed mode and one through a strictly competitive mode. A ratio of the K ii and K is values was used to assess the relative competitiveness of each inhibitor. For the mixed inhibitors, the mode of inhibition varied from mostly uncompetitive to predominantly competitive (K ii /K is values ranging from 0.1 to 15). The implications for potential drug-drug interactions and inhibition mechanism are discussed. We found two inhibitors, clozapine and chlorpromazine, that have a moderate predicted risk of drug-drug interactions based on the K i value relative to the inhibitor concentration in human plasma, having a calculated [I]/K i value of 0.4 and 0.8, respectively.

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“…Lactam formation from an aliphatic carbon-nitrogen bond has been shown to be due to the sequential action of MAO-B (Chiba et al, 1985), or P450 (Cashman et al, 1992), followed by oxidation of the resulting imine by cytosolic AO (Brandlänge and Lindblom, 1979;Yoshihara and Ohta, 1998;Vickers and Polsky, 2000). The presence of residual AO activity in the microsomal and mitochondrial fractions precludes eliminating the involvement of this enzyme in the formation of M12.…”

Section: O Glucmentioning

confidence: 99%

In Vitro Metabolism of the Analgesic Bicifadine in the Mouse, Rat, Monkey, and Human

Erickson

Hollfelder²,

Tenge³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The in vitro metabolism of [ 14 C]bicifadine by hepatic microsomes and hepatocytes from mouse, rat, monkey, and human was compared using radiometric high-performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Two main metabolic pathways were identified in all four species. One pathway was an NADPH-dependent pathway in which the methyl group was oxidized to form a hydroxymethyl metabolite (M2). Its formation was inhibited in human microsomes only by quinidine, a CYP2D6 inhibitor. In incubations with individual cDNA-expressed human cytochromes P450, M2 was formed only by CYP2D6 and CYP1A2, with CYP2D6 activity 6-fold greater than that of CYP1A2.

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The enzyme “aldehyde oxidase” is an iminium oxidase. Reaction with nicotine Δ1′(5′) iminium ion

Cited by 100 publications

References 13 publications

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Recent density functional theory model calculations of drug metabolism by cytochrome P450

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

In Vitro Metabolism of the Analgesic Bicifadine in the Mouse, Rat, Monkey, and Human

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