Human superoxide dismutase 1 attenuates quinoneimine metabolite formation from mefenamic acid

Ogiso, Takuo; Fukami, Tatsuki; Cheng, Zhongzhe; Konishi, Keigo; Nakajima, Miki

doi:10.1016/j.tox.2020.152648

Cited by 3 publications

(1 citation statement)

References 52 publications

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“…In general, quinones and quinoneimines are detoxified by conjugation with glutathione abundantly present in normal human liver (73)(74)(75). In addition, our recent study revealed that superoxide dismutase 1 has the potential to decrease the formation of quinoneimines from drugs such as mefenamic acid in the normal human liver (76). Since expression of NQO1 in the human liver is induced by activated Nrf2 in response to oxidative stress (77), NQO1 may play roles in the detoxification of quinones or quinoneimines from drugs to prevent the exacerbation of liver injury.…”

Section: Nad(p)h:quinone Oxidoreductasementioning

confidence: 99%

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Fukami

Yokoi

Nakajima

2022

Annu. Rev. Pharmacol. Toxicol.

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Most clinically used drugs are metabolized in the body via oxidation, reduction, or hydrolysis reactions, which are considered phase I reactions. Cytochrome P450 (P450) enzymes, which primarily catalyze oxidation reactions, contribute to the metabolism of over 50% of clinically used drugs. In the last few decades, the function and regulation of P450s have been extensively studied, whereas the characterization of non-P450 phase I enzymes is still incomplete. Recent studies suggest that approximately 30% of drug metabolism is carried out by non-P450 enzymes. This review summarizes current knowledge of non-P450 phase I enzymes, focusing on their roles in controlling drug efficacy and adverse reactions as an important aspect of drug development. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Nad(p)h:quinone Oxidoreductasementioning

confidence: 99%

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Fukami

Yokoi

Nakajima

2022

Annu. Rev. Pharmacol. Toxicol.

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Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts

Liu,

Yang,

Zhang

et al. 2024

Expert Opinion on Drug Metabolism & Toxicology

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Characterization of human alcohol dehydrogenase 4 and aldehyde dehydrogenase 2 as enzymes involved in the formation of 5-carboxylpirfenidone, a major metabolite of pirfenidone

Sato,

Fukami,

Shimomura

et al. 2025

Drug Metabolism and Disposition

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Pirfenidone (PIR) is used to treatment of idiopathic pulmonary fibrosis. After oral administration, it is metabolized by cytochrome P450 1A2 to 5-hydroxylpirfenidone (5-OH PIR) and further oxidized to 5-carboxylpirfenidone (5-COOH PIR), a major metabolite excreted in the urine (90% of the dose). This study aimed to identify enzymes that catalyze the formation of 5-COOH PIR from 5-OH PIR in the human liver. 5-COOH PIR was formed from 5-OH PIR in the presence of NAD + by human liver microsomes (HLM) more than by human liver cytosol (HLC), with the concomitant formation of the aldehyde form (5-CHO PIR) as an intermediate metabolite. By purifying enzymes from HLM, alcohol dehydrogenases (ADHs) were identified as candidate enzymes catalyzing 5-CHO PIR formation, although ADHs are localized in the cytoplasm. Among constructed recombinant ADH1-5 expressed in HEK293T cells, only ADH4 efficiently catalyzed 5-CHO PIR formation from 5-OH PIR with a K m value (29.0 ± 4.9 µM), which was close to that by HLM (59.1 ± 4.6 µM). In contrast to commercially available HLC, in-house prepared HLC clearly showed substantial 5-CHO PIR formation, and ADH4 protein levels were significantly (rs = 0.772, P < 0.0001) correlated with 5-CHO PIR formation in 25 in-house prepared HLC samples. Some components of the commercially available HLC may inhibit ADH4 activity.Disulfiram, an inhibitor of aldehyde dehydrogenases (ALDH), decreased 5-COOH PIR formation and increased 5-CHO PIR formation from 5-OH PIR in HLM. ALDH2 knockdown in HepG2 cells by siRNA decreased 5-COOH PIR formation by 61%.

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Human superoxide dismutase 1 attenuates quinoneimine metabolite formation from mefenamic acid

Cited by 3 publications

References 52 publications

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Non-P450 Drug-Metabolizing Enzymes: Contribution to Drug Disposition, Toxicity, and Development

Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts

Characterization of human alcohol dehydrogenase 4 and aldehyde dehydrogenase 2 as enzymes involved in the formation of 5-carboxylpirfenidone, a major metabolite of pirfenidone

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