Identification of enzymes responsible for nitrazepam metabolism and toxicity in human

Konishi, Keigo; Fukami, Tatsuki; Gotoh, Saki; Nakajima, Miki

doi:10.1016/j.bcp.2017.06.114

Cited by 28 publications

(13 citation statements)

References 46 publications

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“…AOX oxidative substrates include aldehydes, aromatic heterocycles, iminium ions, and azaheterocycles; AOX reductive substrates include sulfoxides, nitro compounds, N-oxides, nitrates, nitrites, and molecular oxygen (Krenitsky et al, 1972;Kitamura and Tatsumi, 1984;Stoddart and Levine, 1992;Li et al, 2009b;Pryde et al, 2010;Maia et al, 2015). AOX reductions have been gaining attention (Konishi et al, 2017;Paragas et al, 2017a;Amano et al, 2018). Previously, it was believed that AOX reduction occurs only under anaerobic conditions (Li et al, 2009a;Weidert et al, 2014;Maia et al, 2015), but it has been shown that reduction by AOX can also occur under normal oxygen condition and at a different site than where substrate oxidation happens.…”

Section: Introductionmentioning

confidence: 99%

Time Course of Aldehyde Oxidase and Why It Is Nonlinear

et al. 2019

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Many promising drug candidates metabolized by aldehyde oxidase (AOX) fail during clinical trial owing to underestimation of their clearance. AOX is species-specific, which makes traditional allometric studies a poor choice for estimating human clearance. Other studies have suggested using half-life calculated by measuring substrate depletion to measure clearance. In this study, we proposed using numerical fitting to enzymatic pathways other than Michaelis-Menten (MM) to avoid missing the initial high turnover rate of product formation. Here, product formation over a 240-minute time course of six AOX substrates-, and zoniporide-have been provided to illustrate enzyme deactivation over time to help better understand why MM kinetics sometimes leads to underestimation of rate constants. Based on the data provided in this article, the total velocity for substrates becomes slower than the initial velocity by 3.1-, 6.5-, 2.9-, 32.2-, 2.7-, and 0.2-fold, respectively, in human expressed purified enzyme, whereas the K m remains constant. Also, our studies on the role of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, show that ROS did not significantly alter the change in enzyme activity over time. Providing a new electron acceptor, 5-nitroquinoline, did, however, alter the change in rate over time for mumerous compounds. The data also illustrate the difficulties in using substrate disappearance to estimate intrinsic clearance.

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Section: Introductionmentioning

confidence: 99%

Time Course of Aldehyde Oxidase and Why It Is Nonlinear

et al. 2019

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“…Five microliters of the supernatant was subjected to LC-MS/MS. The concentrations of nitrazepam and aminonitrazepam were measured according to a previously reported method (Konishi et al, 2017).…”

Section: Measurement Of Plasma Concentrations Of Nitrazepam and Amino...mentioning

confidence: 99%

Methionine Sulfoxide Reductase A in Human and Mouse Tissues is Responsible for Sulindac Activation, Making a Larger Contribution than the Gut Microbiota

et al. 2022

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ABBREVIATIONS: AKR, aldo-keto reductase; AOX1, aldehyde oxidase 1; AUC, area under the curve; CL int , intrinsic clearance; C max , maximum plasma concentration; DTT, dithiothreitol; HIC, human intestinal cytosol; HIM, human intestinal microsomes; HLC, human liver cytosol; HLM, human liver microsomes; HRC, human renal cytosol; HRM, human renal microsomes; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MNA, N-methylnicotinamide; MSR, methionine sulfoxide reductase; NSAID, nonsteroidal anti-inflammatory drug; SDR, short-chain dehydrogenases/reductases; TXN, thioredoxin; TXNR, thioredoxin reductase; T max , time of maximum plasma concentration This article has not been copyedited and formatted. The final version may differ from this version.

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“…Several other potentially important amino acid differences, especially the K661E at the gate 1 of the substrate access channel, as well as L812F which is another important amino acid difference pointing to the entrance of the active site pocket still remain to be considered at the MoCo site of AO (Coelho et al, 2015). However, recent publications regarding the AO nitro reduction, most notably the one by Paragas et al in which the FAD site has been suggested as the reductive site of this enzyme, has brought up the possibility of amino acids at this site also having an important role in causing this marked kinetic difference between the two species (Konishi et al, 2017;Paragas et al, 2017a;Amano et al, 2018;Ogiso et al, 2018). However, it is also important to note that there are two sites involved in playing this catalytic see-saw.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Until recently it was believed that reduction of other substrates, such as the ones containing nitro groups, by AO would only happen under anaerobic conditions (Li et al, 2009;Weidert et al, 2013;Maia et al, 2015). However, quite a few examples of aerobic nitro reduction have been presented in the literature in the past few years (Konishi et al, 2017;Amano et al, 2018;Ogiso et al, 2018). This has in turn brought up the possibility of a competition between the reductive substrates and the molecular oxygen at the FAD site (Paragas et al, 2017a).…”

Section: Introductionmentioning

confidence: 99%