Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

Yokota, Shinichi; Higashi, Eriko; Fukami, Tatsuki; Yokoi, Tsuyoshi; Nakajima, Miki

doi:10.1016/j.bcp.2010.09.020

Cited by 34 publications

(24 citation statements)

References 28 publications

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“…In the first step (phase I) drugs are functionalized to make them more reactive. The common reactions in this phase are oxidation, reduction or hydrolysis and are catalyzed by enzymes that can be induced by Nrf2, such as cytochrome P450 (Abu-Bakar et al, 2007;Yokota et al, 2011); aldoketo reductases (AKR) (Ellis, 2007) or NAD(P)H:quinone oxidoreductase 1 (NQO1) (Venugopal and Jaiswal, 1996), (considered a broad antioxidant and cytoprotector; Dinkova-Kostova and Talalay, 2010). During phase II detoxification, xenobiotics are subjected to conjugation with different polar compounds, such as glutathione (GSH), glucuronic acid or a sulfonic group.…”

Section: Introductionmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

139

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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Section: Introductionmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

139

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“…Nongenetic factors contributing to this variability have been proposed, including administration of drugs, exposure to environmental chemicals, diet, and sex hormone (Al Koudsi et al, 2010). These can be partly explained by the activation of transcriptional factors such as pregnane X receptor (Itoh et al, 2006), glucocorticoid receptor (Onica et al, 2008), nuclear factorerythroid 2-related factor 2 (Yokota et al, 2011), and estrogen receptor (Higashi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

CYP2A7 Pseudogene Transcript Affects CYP2A6 Expression in Human Liver by Acting as a Decoy for miR-126*

et al. 2015

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Human cytochrome P450 (CYP)2A6 is responsible for the metabolic activation of tobacco-related nitrosamines, as well as the metabolism of nicotine and some pharmaceutical drugs. There are large interindividual differences in CYP2A6 activity and expression, largely attributed to genetic polymorphisms. However, the variability was observed within homozygotes of the wild-type CYP2A6 gene. In this study, we investigated the possibility that CYP2A6 might be regulated by microRNA. A luciferase assay revealed that a microRNA recognition element (MRE) of miR-126* found in the 39-untranslated region (UTR) of CYP2A6 mRNA is functional. We established two HEK293 cell lines stably expressing CYP2A6, with one including and the other excluding the full-length 39-UTR (HEK/ 2A6+UTR and HEK/2A6 cells, respectively). Overexpression of miR-126* markedly decreased CYP2A6 protein levels, enzyme activity, and mRNA level in HEK/2A6+UTR cells, whereas it marginally decreased those in HEK/2A6 cells, indicating that the 39-UTR including the MRE is functional for the downregulation of CYP2A6 by miR-126*. The inhibition of miR-126* increased CYP2A6 protein levels in primary human hepatocytes, suggesting that miR-126* downregulates endogenous CYP2A6 expression. In 20 human liver samples, the expression ratios of CYP2A6 and a pseudogene transcript CYP2A7 mRNA were highly variable (CYP2A7/CYP2A6: 0.1 to 12). Interestingly, we found that CYP2A7 was another target of miR-126* and restored the miR-126*-dependent downregulation of CYP2A6 by acting as a decoy for miR-126*. In conclusion, this study demonstrates that human CYP2A6 is post-transcriptionally regulated by miR-126* and that CYP2A7 affects CYP2A6 expression by competing for miR-126* binding.

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“…In the present study, a similar decrease in GSH levels was observed in ethanol-treated WT mice and cyp2a5 −/− mice; thus, other Nrf2-regulated mechanisms may be involved. CYP2A6, the human orthologue to CYP2A5, is regulated by Nrf2 (7, 30). Recently, we found that the ethanol induction of CYP2A5 occurs through a CYP2E1-ROS-Nrf2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice

Hong

Liu

Ward

et al. 2015

Digestive and Liver Disease

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Background Ethanol can induce cytochrome P450 2E1, an active generator of reactive oxygen species, and this cytochrome is considered a risk factor for oxidative liver injury. Recently, we found that in addition to P450 2E1 also cytochrome P450 2A5, another isoform of cytochrome P450, can be induced by ethanol, and that ethanol induction of cytochrome P450 2A5 is P450 2E1-dependent. Aims To investigate the role of cytochrome P450 2A5 in alcohol-induced liver injury. Methods Cytochrome P450 2A5-knockout mice and wild type mice were fed the Lieber-Decarli ethanol liquid diet to induce liver injury. Controls were fed the Lieber-Decarli control diet. Results After 4 weeks of feeding with Lieber-Decarli diet, ethanol-induced liver injury was enhanced in the knockout mice compared with wild type mice, as indicated by serum transaminases, hepatic fat accumulation (steatosis), and necroinflammation observed in liver sections with Haematoxylin & Eosin staining. Ethanol-induced oxidative stress was also higher in the knockout mice than the wild types. Ethanol feeding induced cytochrome P450 2A5 in wild type mice but not in the knockout mice, while induction of cytochrome P450 2E1 was comparable in the knockout and wild type mice. Conclusion These results suggest that cytochrome P450 2A5 protects against ethanol-induced oxidative liver injury.

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Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

Cited by 34 publications

References 28 publications

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

CYP2A7 Pseudogene Transcript Affects CYP2A6 Expression in Human Liver by Acting as a Decoy for miR-126*

Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice

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