Myocardial pharmacokinetics of ebastine, a substrate for cytochrome P450 2J, in rat isolated heart

Kang, Wonku; Elitzer, S; Noh, Keumhan; Bednarek, Tobias; Weiß, Michael

doi:10.1111/j.1476-5381.2011.01338.x

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…Therefore, we first measured NADPH oxidation by CYP2J2‐CPR‐ND in presence of ebastine. CYP2J2 is mainly responsible for the hydroxylation of the H1‐receptor antagonist ebastine in human liver and intestinal microsomes . We observed that NADPH oxidation was the greatest in 20% POPS discs, followed closely by 40% POPS discs [Fig.…”

Section: Resultsmentioning

confidence: 96%

Lipid composition and macromolecular crowding effects on CYP2J2‐mediated drug metabolism in nanodiscs

2019

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Lipid composition and macromolecular crowding are key external effectors of protein activity and stability whose role varies between different proteins. Therefore, it is imperative to study their effects on individual protein function. CYP2J2 is a membrane-bound cytochrome P450 in the heart involved in the metabolism of fatty acids and xenobiotics. In order to facilitate this metabolism, cytochrome P450 reductase (CPR), transfers electrons to CYP2J2 from NADPH. Herein, we use nanodiscs to show that lipid composition of the membrane bilayer affects substrate metabolism of the CYP2J2-CPR nanodisc (ND) system. Differential effects on both NADPH oxidation and substrate metabolism by CYP2J2-CPR are dependent on the lipid composition. For instance, sphingomyelin containing nanodiscs produced more secondary substrate metabolites than discs of other lipid compositions, implying a possible conformational change leading to processive metabolism. Furthermore, we demonstrate that macromolecular crowding plays a role in the lipid-solubilized CYP2J2-CPR system by increasing the K m and decreasing the V max , and effect that is size-dependent. Crowding also affects the CYP2J2-CPR-ND system by decreasing both the K m and V max for Dextran-based macromolecular crowding agents, implying an increase in substrate affinity but a lack of metabolism. Finally, protein denaturation studies show that crowding agents destabilize CYP2J2, while the multidomain protein CPR is stabilized. Overall, these studies are the first report on the role of the surrounding lipid environment and macromolecular crowding in modulating enzymatic function of CYP2J2-CPR membrane protein system. Additional Supporting Information may be found in the online version of this article. Statement of importance:This work is of interest to researchers studying macromolecular crowding, protein-lipid interactions, and cytochrome P450s. This work provides key insights into the kinetic effects of lipid composition as well as macromolecular crowding, a constant force within any cell. We also determine the effects of a crowded environment on membrane protein stability. As CYPs are important drug metabolizers, such data are pertinent to current and future studies.

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Section: Resultsmentioning

confidence: 96%

Lipid composition and macromolecular crowding effects on CYP2J2‐mediated drug metabolism in nanodiscs

2019

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“…Furthermore, in isolated rat heart hydroxylation of the H 1 receptor antagonist, ebastine to hydroxyebastine and carebastine was detected and compared with human liver microsomes and showed a similar metabolism profile; however, as there was no comparison with metabolism in the human heart, it is difficult to ascertain comparative activity between CYP2J2 CYP2J2 and Cardiotoxicity and CYP2J3. It is also unclear whether other P450 enzymes could be responsible, in part, for ebastine metabolism (Kang et al, 2011). Overall, the metabolic activity of CYP2J2 in the liver and its ability to metabolize a wide array of drugs, coupled with its high expression in the heart, warrant further studies to clarify the significance of cardiac CYP2J2 in drug metabolism in physiologic relevant systems.…”

Section: Humanmentioning

confidence: 99%

Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity

et al. 2018

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Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.

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