title: Genotype-dependent down-regulation of gene expression and function of MDR1 in human peripheral blood mononuclear cells under acute inflammation.
abstract: Recent advances in pharmacogenomics have suggested the association of clinical outcome of glucocorticoid-based anti-inflammatory therapy with a single nucleotide polymorphism at position 3435 in exon 26 (C3435T) of the MDR1 gene. In the present study, the effects of the MDR1 C3435T genotype on the time-dependent profiles of gene expression and function of MDR1/P-glycoprotein were evaluated in peripheral blood mononuclear cells (PBMCs) under lipopolysaccharide (LPS)-induced experimental acute inflammation. LPS treatment resulted in the rapid elevation of IL-1beta and TNF-alpha mRNA levels relative to beta-actin mRNA at 1 h, with a subsequent slight decrease at 3 h after the treatment, while the down-regulation of the relative concentration of MDR1 mRNA was found at 3 h, not at 1 h, after LPS treatment. Here, the C3435T genotype-dependent down-regulations of MDR1 mRNA level were found for CC(3435) and CT(3435), but not for TT(3435), and were 64.1+/-10.1%, 71.4+/-5.9% and 100.0+/-22.5% (+/-S.D.), respectively, of their respective baseline levels, which were independent of C3435T (0.010+/-0.005, 0.011+/-0.013 and 0.009+/-0.006 (+/-S.D.), respectively). The C3435T genotype-dependent down-regulation was supported by the increase of the intracellular accumulation of calcein in PBMCs treated with LPS for 72 h, and the increase was more predominant for CC(3435) than TT(3435). These data suggested that glucocorticoid-based anti-inflammatory therapy might be more effective for C(3435)-allele carriers than non-carriers.
authors.affiliation: Division of Clinical Pharmacokinetics, Kobe University Graduate School of Medicine, Japan.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Markova
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Hiroo
authors.initials: H
authors.lastname: Makimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Uchiyama
authors.forename: Noboru
authors.initials: N
authors.lastname: Okamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000208:Acute Disease; D000328:Adult; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D005452:Fluoresceins / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000503:physiopathology*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C007740:fluorexon