Expression and inducibility of CYP1A1, 1A2, 1B1 by β-naphthoflavone and CYP2B22, 3A22, 3A29, 3A46 by rifampicin in the respiratory and olfactory mucosa of pig

Messina, Andréa; Nannelli, Annalisa; Fiorio, R.; Longo, Vincenzo; Gervasi, Pier Giovanni

doi:10.1016/j.tox.2009.03.003

Cited by 31 publications

(19 citation statements)

References 37 publications

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“…We detected transcripts of the receptors AhR, PPAR␣, PXR, and GR. However, in agreement with a recent report (Messina et al, 2009), no CAR expression was detected in this tissue. The transcription factor Nrf2 was found to be expressed in high amounts in the OM.…”

Section: Discussionsupporting

confidence: 94%

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Effects of Typical Inducers on Olfactory Xenobiotic-Metabolizing Enzyme, Transporter, and Transcription Factor Expression in Rats

Thiebaud¹,

Sigoillot²,

Chevalier³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Several xenobiotic-metabolizing enzymes (XMEs) have been identified in the olfactory mucosa (OM) of mammals. However, the molecular mechanisms underlying the regulation of these enzymes have been little explored. In particular, information on the expression of the transcriptional factors in this tissue is quite limited. The aim of the present study was to examine the impact of five typical inducers, Aroclor 1254, 3-methylcholanthrene, dexamethasone, phenobarbital, and ethoxyquin, on the activities and mRNA expression of several XMEs in the OM and in the liver of rats. We also evaluated the effects of these treatments on the mRNA expression of transcription factors and transporters. On the whole, the intensities of the effects were lower in the OM than in the liver. Dexamethasone was found to be the most efficient treatment in the OM. Dexamethasone induced the transcription of several olfactory phase I, II, and III genes [such as cytochromes P450 2A3 and 3A9, UDP-glucuronosyltransferase (UGT) 2A1, and multidrug resistance-related protein type 1] and increased UGT activities. We observed that dexamethasone up-regulated sulfotransferase 1C1 expression in the OM but down-regulated it in the liver. Aroclor and ethoxyquin induced the gene expression of CYP1A and quinone reductase, respectively, in the OM. The transcription factors aryl hydrocarbon receptor, nuclear factor E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor ␣, pregnane X receptor, and glucocorticoid receptor were detected in the OM, but no constitutive androstane receptor expression was observed. Dexamethasone and Aroclor enhanced olfactory Nrf2 expression. These results demonstrate that olfactory XME can be modulated by chemicals and that the mechanisms involved in the regulation of these enzymes are tissue-specific.

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Section: Discussionsupporting

confidence: 94%

“…The molecular mechanisms underlying the induction of olfactory XME have been poorly explored. Only one study reports the expression of the nuclear receptors PXR and AhR in pig OM (Messina et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Effects of Typical Inducers on Olfactory Xenobiotic-Metabolizing Enzyme, Transporter, and Transcription Factor Expression in Rats

Thiebaud¹,

Sigoillot²,

Chevalier³

et al. 2010

Drug Metab Dispos

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“…As shown in Fig. 2 and Table 2, compared with vehicle control, nine drugs, i.e., beclomethasone, finasteride, flunisolide, fluticasone propionate, megestrol acetate, nimodipine, nisoldipine, secobarbital, and aminoglutethimide, showed noticeable increases of hPXR-mediated CYP2B6 reporter activities at 10 M. RIF is an established hPXR activator (Cheng et al, 2009;Messina et al, 2009). Among the active molecules, fluticasone propionate and nimodipine exhibited robust hPXR activation to a level that challenges that of RIF, whereas nisoldipine was not as potent as RIF but still caused a significant increase in hPXR-mediated CYP2B6 reporter activities.…”

Section: Resultsmentioning

confidence: 90%

Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

Pan

Li²,

Gregory³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human pregnane X receptor (hPXR) plays a key role in regulating metabolism and clearance of endogenous and exogenous substances. Identification of novel hPXR activators among commercial drugs may aid in avoiding drug-drug interactions during coadministration. We applied ligand-based computational approaches for virtual screening of a commonly prescribed drug database (SCUT). Bayesian classification models were generated with a training set comprising 177 compounds using Fingerprints and 117 structural descriptors. A cell-based luciferase reporter assay was used for evaluation of chemical-mediated hPXR activation in HepG2 cells. All compounds were tested at 10 M concentration with rifampicin and dimethyl sulfoxide as positive and negative controls, respectively. The Bayesian models showed specificity and overall prediction accuracy up to 0.92 and 0.69 for test set compounds. Screening the SCUT database with this model retrieved 105 hits and 17 compounds from the top 25 hits were chosen for in vitro testing. The reporter assay confirmed that nine drugs, i.e., fluticasone, nimodipine, nisoldipine, beclomethasone, finasteride, flunisolide, megestrol, secobarbital, and aminoglutethimide, were previously unidentified hPXR activators. Thus, the present study demonstrates that novel hPXR activators can be efficiently identified among U.S. Food and Drug Administrationapproved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.

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“…Thus, mRNA of several CYP isoforms was elevated in pigs treated with beta-naphthoflavone (β-NF) as 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 27 compared with the control animals. Specifically, the level of CYP1A1 mRNA was increased in the heart regions 141 as well as liver, respiratory tissues, and olfactory tissues of pigs 142 . The level of mRNA of CYP1A2 and CYP1B1 was only increased in the liver.…”

Section: Polyphenols-mediated Modulation Of Cyp Gene Expressionmentioning

confidence: 95%

“…The level of mRNA of CYP1A2 and CYP1B1 was only increased in the liver. 142 Significant changes in the expression of CYP proteins were observed in male Wistar rats treated with soybean extract containing 37% isoflavones, specifically genistein and daidzein. 103 After 10 days of treatment, the expression of CYP1A1 and CYP2D1 was increased by 50% and 32%, respectively, compared with the control group of animals.…”

Section: Polyphenols-mediated Modulation Of Cyp Gene Expressionmentioning

confidence: 98%

Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases

Korobkova

2015

Chem. Res. Toxicol.

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Cytochromes P450 (CYPs) are a large group of hemeproteins located on mitochondrial membranes or the endoplasmic reticulum. They play a crucial role in the metabolism of endogenous and exogenous molecules. The activity of CYP is associated with a number of factors including redox potential, protein conformation, the accessibility of the active site by substrates, and others. This activity may be potentially modulated by a variety of small molecules. Extensive experimental data collected over the past decade point at the active role of natural polyphenols in modulating the catalytic activity of CYP. Polyphenols are widespread micronutrients present in human diets of plant origin and in medicinal herbs. These compounds may alter the activity of CYP either via direct interactions with the enzymes or by affecting CYP gene expression. The polyphenol-CYP interactions may significantly alter the pharmacokinetics of drugs and thus influence the effectiveness of chemical therapies used in the treatment of different types of cancers, diabetes, obesity, and cardiovascular diseases (CVD). CYPs are involved in the oxidation and activation of external carcinogenic agents, in which case the inhibition of the CYP activity is beneficial for health. CYPs also support detoxification processes. In this case, it is the upregulation of CYP genes that would be favorable for the organism. A CYP enzyme aromatase catalyzes the formation of estrone and estradiol from their precursors. CYPs also catalyze multiple reactions leading to the oxidation of estrogen. Estrogen signaling and oxidative metabolism of estrogen are associated with the development of cancer. Thus, polyphenol-mediated modulation of the CYP's activity also plays a vital role in estrogen carcinogenesis. The aim of the present review is to summarize the data collected over the last five to six years on the following topics: (1) the mechanisms of the interactions of CYP with food constituents that occur via the direct binding of polyphenols to the enzymes and (2) the mechanisms of the regulation of CYP gene expression mediated by polyphenols. The structure-activity relationship relevant to the ability of polyphenols to affect the activity of CYP is analyzed. The application of polyphenol-CYP interactions to diseases is discussed.

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Expression and inducibility of CYP1A1, 1A2, 1B1 by β-naphthoflavone and CYP2B22, 3A22, 3A29, 3A46 by rifampicin in the respiratory and olfactory mucosa of pig

Cited by 31 publications

References 37 publications

Effects of Typical Inducers on Olfactory Xenobiotic-Metabolizing Enzyme, Transporter, and Transcription Factor Expression in Rats

Effects of Typical Inducers on Olfactory Xenobiotic-Metabolizing Enzyme, Transporter, and Transcription Factor Expression in Rats

Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases

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