Peroxisome Proliferator-Activated Receptors in Regulation of Cytochromes P450: New Way to Overcome Multidrug Resistance?

Čížková, Kateřina; Konieczna, Anna; Erdösová, Běla; Lichnovská, Radka; Ehrmann, Jiří

doi:10.1155/2012/656428

Cited by 19 publications

(14 citation statements)

References 53 publications

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“…1), implicating the role of these particular isoforms in OLAM formation. There are several reports of CYP2J and CYP3A expression in immune cells where these enzymes are believed to play a role in drug metabolism, steroid synthesis, angiogenesis, mitogenesis, cell signaling, etc [5,7,21,27,35]. Our study is the first to report that these CYPs in immune cells may also regulate peripheral pain pathways, thus, being potential candidates for peripherally acting analgesics for inflammatory conditions.…”

Section: Discussionmentioning

confidence: 56%

Oxidized linoleic acid metabolite–cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain

Ruparel

Hargreaves

Eskander

et al. 2013

Pain

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Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [e.g., cytochrome P450 (CYP)], are up-regulated following inflammation in the rat. However, it is not known if such agonists are elevated in human inflammatory pain conditions. Since TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal versus inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues, evoked significant inward currents in TG neurons, and were blocked by pretreatment with the TRPV1 antagonist, IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in TG neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of two CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicates that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.

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Section: Discussionmentioning

confidence: 56%

Oxidized linoleic acid metabolite–cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain

Ruparel

Hargreaves

Eskander

et al. 2013

Pain

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“…fenofibrate, bezafibrate, gemfibrozil) are used for hyperlipidaemia, diabetes and metabolic syndrome treatment. Moreover, the non-steroidal anti-inflammatory drug indomethacin and anticonvulsants such as phenobarbital and valproic acid activate this receptor [2]. In addition, various environmental contaminants activate PPARa, for example phtalates, tri-and dichloracetic acids, trichlorethylene and the perfluoroalkyl acid compounds (PFAAs) such as perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorooctanesulfonate (PFOS).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, their transcriptional activity can also be modulated by cross-talk between phosphorylation and dephosporylation. The effect of these modifications depends on cellular context, receptor type and residue metabolized [2].PPARa is activated by a wide range of both endogenous and exogenous ligands, such as dietary fatty acids, eicosanoids, hypolipidaemic drugs, phthalates, pesticides, etc. The receptor is highly expressed in tissues with active fatty acid metabolism, such as the liver, heart muscle, intestine and kidney.…”

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confidence: 99%

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Spatio‐Temporal Expression of Peroxisome Proliferator‐Activated Receptor α During Human Prenatal Development

Čížková

Rajdová

Ehrmann

2014

Basic Clin Pharma Tox

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Peroxisome proliferator-activated receptor a (PPARa) is a ligand-dependent transcription factor which is activated by various endogenous as well as exogenous compounds. It is involved in the regulation of a variety of biological processes, such as nutrient metabolism, energy homoeostasis, immunological response and xenobiotic metabolism. Little is known about its expression during human prenatal development. We examined the spatio-temporal expression pattern of PPARa in human embryonic/foetal intestines, liver and kidney from the 5th to 20th week of prenatal life by indirect two-step immunohistochemistry. PPARa expression can already be detected in the early stages of prenatal development; as early as the 7th week of intrauterine development (IUD) in the intestines, 5th week of IUD in the liver and 6th week of IUD in the kidney. We found agedependent changes in the PPARa expression pattern in the intestines and kidney. These events occur approximately at the commencement of function of these organs. In the intestines, we detected an obvious change of the PPARa expression pattern along the crypt-villous axis in the 11th week of IUD. In the kidney, the most apparent change was increased expression of PPARa in glomeruli in the 12th week of IUD. Moreover, in the liver, we detected a strong positivity in part of the developing blood elements. Information about the spatio-temporal expression pattern of PPARa could be the first step in evaluating the potential harmful impact of a wide range of environmental or pharmaceutical compounds which serve as PPARa ligands on the developing human organism.Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that belong to the nuclear receptor superfamily. PPARs consist of three members: peroxisome proliferator-activated receptor a (PPARa), PPARb/d and PPARc. The receptors are encoded by different genes and activated by different compounds. PPARa is well known as a regulator of nutrient metabolism and energy homoeostasis. Moreover, it is involved in the regulation of inflammation and immune response as well as xenobiotic metabolism [1]. After ligand binding, PPARs bind to the peroxisome proliferator response element in the promoter region of target genes as a heterodimer with retinoid X receptor (RXR). Beside ligands, the receptors interact with a huge number of co-activators and co-repressors. Furthermore, their transcriptional activity can also be modulated by cross-talk between phosphorylation and dephosporylation. The effect of these modifications depends on cellular context, receptor type and residue metabolized [2].PPARa is activated by a wide range of both endogenous and exogenous ligands, such as dietary fatty acids, eicosanoids, hypolipidaemic drugs, phthalates, pesticides, etc. The receptor is highly expressed in tissues with active fatty acid metabolism, such as the liver, heart muscle, intestine and kidney. Inappropriate activation of the receptor during prenatal development by xenobiotics can alter gene expression. ...

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“…In contrary, PPAR pathways in rainbow trout were not activated by the fibrate drug gemfibrozil (Prindiville et al, 2011). Given that PPARs, especially PPARα, might control some CYP450 isoforms (Cizkova et al, 2012) and expression of Phase II enzymes, it is likely that changes in PPAR expression caused by pharmaceuticals will in turn affect metabolism of xenobiotics.…”

Section: Blood-lipid-lowering Pharmaceuticalsmentioning

confidence: 99%

Effects of pharmaceuticals present in aquatic environment on Phase I metabolism in fish

Burkina

Žlábek

Zamaratskaia

2015

Environmental Toxicology and Pharmacology

122

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Peroxisome Proliferator-Activated Receptors in Regulation of Cytochromes P450: New Way to Overcome Multidrug Resistance?

Cited by 19 publications

References 53 publications

Oxidized linoleic acid metabolite–cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain

Oxidized linoleic acid metabolite–cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain

Spatio‐Temporal Expression of Peroxisome Proliferator‐Activated Receptor α During Human Prenatal Development

Effects of pharmaceuticals present in aquatic environment on Phase I metabolism in fish

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