Involvement of C3435T and G2677T multidrug resistance gene polymorphisms in release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone.
P-Glycoprotein is a cell membrane-associated protein that transports a variety of exogenous (including drugs) and endogenous substances. P-Glycoprotein may also be involved in transmembrane transport of some endogenous proteins; thus, it may have physiological function in cytokine transport. Previous studies suggested that P-glycoprotein expression is genetically determined. The aim of this study was to examine involvement of multidrug resistance gene (MDR1) C3435T and G2677T polymorphisms in release of cytokines from phythemaglutynin (PHA)-stimulated peripheral blood mononuclear cells, as well as treated with methotrexate or dexamethasone. The release of cytokines: interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-gamma (INF-gamma) and tumor necrosis factor-alpha (TNF-alpha) was determined in supernatants of mononuclear cell cultures from 72 healthy subjects, measured by flow cytometry. The release of INF-gamma, IL-2, IL-4 and TNF-alpha in cultures from subjects with 2677(T-T) 3435(T-T) haplotype pair was significantly decreased as compared to subjects with other haplotypes. There were no statistically significant differences in release of IL-6 and IL-10. The results of this study suggest an association between C3435T and G2677T MDR1 polymorphisms and transmembrane transport of some cytokines. Although the studied polymorphisms may be in linkage with polymorphisms of other transporters involved in cytokine release, it seems that the present results indirectly indicate involvement of P-glycoprotein in transport of some cytokines. Moreover, determination of C3435T and G2677T MDR1 polymorphisms might be useful in response prediction to therapy with methotrexate and dexamethasone.
Pawlik
Andrzej
A
Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, ul. Powst. Wlkp. 72, Poland. pawand@poczta.onet.pl
Baskiewicz-Masiuk
Magdalena
M
Machalinski
Bogusław
B
Kurzawski
Mateusz
M
Gawronska-Szklarz
Barbara
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology*; D010835:Phytohemagglutinins; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D007371:Interferon-gamma; D008727:Methotrexate