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

Abstract：

BACKGROUND AND PURPOSE: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. EXPERIMENTAL APPROACH: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. KEY RESULTS: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 (IFNgamma) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNgamma 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). CONCLUSIONS AND IMPLICATIONS:These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Liptrott NJ,Penny M,Bray PG,Sathish J,Khoo SH,Back DJ,Owen A

doi

10.1111/j.1476-5381.2008.00050.x

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

497-508

issue

3

eissn

0007-1188

issn

1476-5381

pii

BPH050

journal_volume

156

pub_type

杂志文章

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