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The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC

Liptrott, N. J., Penny, M., Bray, Patrick, Sathish, J., Khoo, S. H., Back, D. J. and Owen, A. (2009) 'The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC'. British Journal of Pharmacology, Vol 156, Issue 3, pp. 497-508.

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Abstract

The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.
Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes.
We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 +/- 11961) and protein (% control 200 +/- 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-gamma (IFN gamma) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFN gamma respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r(2) = 0.545).
These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.

Item Type: Article
Uncontrolled Keywords: ABCB1 (P-glycoprotein) ABCC1 (MRP1) ABCC2 (MRP2) CYP2B6 CYP3A4 CXCR4 CCR5 cytokines peripheral blood mononuclear cell multidrug resistance p-glycoprotein expression necrosis-factor-alpha peripheral-blood lymphocytes human-immunodeficiency-virus rheumatoid-arthritis messenger-rna mononuclear-cells interferon-gamma human liver cancer
Subjects: QW Microbiology and Immunology > Immunity by Type > QW 568 Cellular immunity. Immunologic cytotoxicity. Immunocompetence. Immunologic factors (General)
QU Biochemistry > Biochemistry of the Human Body > QU 100 Body composition
QW Microbiology and Immunology > Immunotherapy and Hypersensitivity > QW 800 Biological products producing immunity
QV Pharmacology > QV 38 Drug action.
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1111/j.1476-5381.2008.00050.x
Depositing User: Mary Creegan
Date Deposited: 24 Jun 2010 14:54
Last Modified: 06 Feb 2018 12:59
URI: https://archive.lstmed.ac.uk/id/eprint/320

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