Cytochrome P450 mono‐oxygenase gene expression and protein activity in cultures of adult cardiomyocytes of the rat

Thum, Thomas; Borlak, Jürgen

doi:10.1038/sj.bjp.0703465

Cited by 61 publications

(33 citation statements)

References 25 publications

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“…The expression of various P450 isozymes in the heart, including CYP1A1, CYP2B6, CYP2C8, CYP2C19, CYP2J2, and CYP2E1, are also reported (Wu et al, 1996;Thum and Borlak, 2000;Michaud et al, 2010). In the cardiac cell line, the expression of CYP2J2 agrees well with previously published data but the cellular expression levels of the CYP2C subfamily were below limits of detection.…”

Section: Discussionsupporting

confidence: 79%

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

et al. 2013

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Cytochrome P450 2J2 plays a significant role in the epoxidation of arachidonic acid to signaling molecules important in cardiovascular events. CYP2J2 also contributes to drug metabolism and is responsible for the intestinal clearance of ebastine. However, the interaction between arachidonic acid metabolism and drug metabolism in cardiac tissue, the main expression site of CYP2J2, has not been examined. Here we investigate an adult-derived human primary cardiac cell line as a suitable model to study metabolic drug interactions (inhibition and induction) of CYP2J2 in cardiac tissue. The primary human cardiomyocyte cell line demonstrated similar mRNA-expression profiles of P450 enzymes to adult human ventricular tissue. CYP2J2 was the dominant isozyme with minor contributions from CYP2D6 and CYP2E1. Both terfenadine and astemizole oxidation were observed in this cell line, whereas midazolam was not metabolized suggesting lack of CYP3A activity. Compared with recombinant CYP2J2, terfenadine was hydroxylated in cardiomyocytes at a similar K m value of 1.5 mM. The V max of terfenadine hydroxylation in recombinant enzyme was found to be 29.4 pmol/pmol P450 per minute and in the cells 6.0 pmol/pmol P450 per minute. CYP2J2 activity in the cell line was inhibited by danazol, astemizole, and ketoconazole in submicromolar range, but also by xenobiotics known to cause cardiac adverse effects. Of the 14 compounds tested for CYP2J2 induction, only rosiglitazone increased mRNA expression, by 1.8-fold. This cell model can be a useful in vitro model to investigate the role of CYP2J2-mediated drug metabolism, arachidonic acid metabolism, and their association to drug induced cardiotoxicity.

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Section: Discussionsupporting

confidence: 79%

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

et al. 2013

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“…Expression of cytochrome P450 mono-oxygenases is reported for extrahepatic tissues including lung, kidney, gastrointestinal tract, endothelium and heart (Thum & Borlak 2000a). Heart tissue is metabolically competent and disease may The levels of the proteins were quantitated using the software ImageJ (NIH, USA) and the pixel intensities are shown as histograms.…”

Section: Discussionmentioning

confidence: 99%

Analysis of differentially expressed genes in hyperthyroid-induced hypertrophied heart by cDNA microarray

Kyle

Ghosh²,

Datta³

et al. 2004

Journal of Endocrinology

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Experiments were carried out to identify the altered genes in hyperthyroid rat heart and their influence on the functions of cardiac myocytes. Chronic treatment of rats with 3,5,3 triiodo--thyronine (T3) resulted in a prominent increase in the size of the left ventricle with increased wall thickness and reduced chamber volume leading to concentric cardiac hypertrophy. The heart weight to body weight ratio (HW/BW) in hyperthyroid rats was increased by about 58% over that of normal rats. Using cDNA microarray comprising 588 genes, we compared the differences in mRNA expression of hyperthyroid and normal rat heart. Based on a threshold of greater than 10% change, about 37 genes were found to be regulated by T3. Further analyses by Western blotting, Northern blotting and real-time quantitative RT-PCR of some of the genes confirmed the microarray results. The T3-altered genes encode various types of proteins related to metabolism, matrix and cytoskeletal structures, growth factors, transcription factors, Ca 2+ -channels etc. The physiological significance of one of these altered proteins in hyperthyroid heart, insulin-responsive glucose transporter (GLUT) type 4 (GLUT4), was studied in detail. The expression of GLUT4 was drastically reduced in the ventricular tissues of hyperthyroid heart. Insulin-induced glucose uptake in hyperthyroid cardiomyocytes was reduced significantly, indicating the impaired glucose transport in cardiac cells. Interestingly, a few genes such as GLUT4, cytochrome P450 isoforms, superoxide dismutase (SOD), collagens, matrix metalloproteinases (MMP), tissue inhibitors of matrix metalloproteinases etc. which had not been reported earlier were found to be altered in hyperthyroid heart. Our results show some new aspects of hyperthyroid heart which will be important in assessing the pathophysiology of hypertrophied cardiomyocytes.

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“…The activation of CYP2E1 by ethanol is one of the main metabolic ethanol pathways and is responsible for the production of oxidative damage in hepatocytes (15). CYP2E1 is also expressed constitutively in isolated rat cardiomyocytes (16). Increased lipid peroxidation and CYP2E1 levels have been observed under chronic ethanol administration.…”

Section: Free Form Bound Form Total ---------------------------------mentioning

confidence: 99%

The sap of Acer okamotoanum decreases serum alcohol levels after acute ethanol ingestion in rats

Yoo

Jung²,

Kang³

et al. 2011

Int J Mol Med

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Abstract. In the present study, we examined whether Acer okamotoanum (A. okamotoanum) sap decreased the serum alcohol and acetaldehyde levels after acute ethanol treatment in a rat model. Male rats were orally administered 25, 50 or 100% A. okamotoanum sap 30 min prior to oral challenge with 3 ml of ethanol (15 ml/kg of a 20% ethanol solution in water), and the blood concentrations of alcohol and acetaldehyde were analyzed up to 7 h after the treatment. Pre-treatment with the sap significantly decreased the blood ethanol and acetaldehyde concentrations after 5 h when compared with ethanol treatment alone (a negative control). The expression levels of liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) mRNA were increased significantly in animals pre-treated with A. okamotoanum sap when compared with negative and positive controls. The data suggest that sap pretreatment enhanced the alcohol metabolism rate in the rat liver. To investigate the involvement of mitochondrial regulation in the ethanol-induced hepatocyte apoptosis, we carried out an immunohistochemical analysis of Bax and Bcl-2. Pre-treatment with sap significantly decreased Bax expression and increased Bcl-2 expression 7 h after ethanol administration when compared with the negative control. The data suggest that A. okamotoanum sap pre-treatment may reduce the alcohol-induced oxidative stress in the rat liver.

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Cytochrome P450 mono‐oxygenase gene expression and protein activity in cultures of adult cardiomyocytes of the rat

Cited by 61 publications

References 25 publications

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

Analysis of differentially expressed genes in hyperthyroid-induced hypertrophied heart by cDNA microarray

The sap of Acer okamotoanum decreases serum alcohol levels after acute ethanol ingestion in rats

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