Genotype-dependent Down-regulation of Gene Expression and Function of MDR1 in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

Markova, Svetlana; Nakamura, Tsutomu; Sakaeda, Toshiyuki; Makimoto, Hiroo; Uchiyama, Hiroo; Okamura, Noboru; Okumura, Katsuhiko

doi:10.2133/dmpk.21.194

Cited by 18 publications

(18 citation statements)

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“…32) In our previous study, it was hypothesized that the ABCB1 C3435T genotype could be a marker for glucocorticoid resistance, because under experimental conditions in LPS-treated PBMC of the subjects harboring the ABCB1 TT 3435 genotype, ABCB1 mRNA and consequently ABCB1 function was significantly down-regulated in comparison to that in those harboring the ABCB1 CC 3435 genotype. 11) In the present study, however, no significant association was found between the ABCB1 CT 3435 genotype and the proinflammatory effect of prednisolone, probably due to an insufficient period of time for a change in ABCB1 function. Future detailed studies are warranted to appropriately investigate this possibility, and are needed to confirm the pro-inflammatory effect of other glucocorticoids under inflammatory conditions, to find possible chains of the mechanism responsible for the pro-inflammatory effect of glucocorticoids, and to examine other possible factors including related genotypes and the presence of unusual transcription factors, which might be involved in the mechanisms.…”

Section: ϫ5contrasting

confidence: 83%

“…The set of primers and the TaqMan probe for IL-1b were designed previously 11) and synthesized by Hokkaido System Science, Co., Ltd. (Sapporo, Japan) and Operon Biotechnologies, Inc. (Tokyo, Japan), respectively. That for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an endogenous RNA control to normalize for differences in the amount of total RNA, was purchased from Applied Biosystems (TaqMan GAPDH Control Reagent Kit; Applied Biosystems, Foster City, CA, U.S.A.).…”

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confidence: 99%

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IL-1.BETA. Genotype-Related Effect of Prednisolone on IL-1.BETA. Production in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

Markova

Nakamura

Makimoto

et al. 2007

Biological & Pharmaceutical Bulletin

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Glucocorticoids are potent anti-inflammatory and immunosuppressive drugs and consequently are widely used in the treatment of systemic inflammatory, allergic, and autoimmune diseases. The anti-inflammatory properties of glucocorticoids are mainly ascribed to their ability to suppress the synthesis of pro-inflammatory cytokines.1) But there is a certain percentage of patients, resistant to glucocorticoid-based anti-inflammatory therapy, who show high levels of local and/or systemic pro-inflammatory cytokines during glucocorticoid treatment. 2,3)IL-1b is considered to trigger a cascade of other pro-inflammatory cytokines and then maintain inflammation. [4][5][6] Therefore, the high inter-individual variation in IL-1b production may result in the different intensity of the inflammatory process among subjects, and possibly may lead to interindividual differences in the response to glucocorticoids. Recent advances in molecular genetics have suggested an association of IL-1b production intensity with genotype, especially with single nucleotide polymorphisms (SNPs) at positions Ϫ1470, Ϫ511, and Ϫ31 in the promoter region and at position 3954 in exon 5 of the IL-1b gene, but results have been inconsistent. There are two reports demonstrating an association of the TT Ϫ31 and CC Ϫ511 genotypes with increased IL-1b mRNA expression and protein release in Japanese 7) and Chinese populations, 8) and one report claiming an association of the TT Ϫ31 and CC Ϫ511 genotypes with less intensive IL-1b production in Caucasians. 9) Also, Pociot et al. 10)found an association between the C3954T polymorphism and IL-1b production, but in later studies by Hall et al. 9) and Kimura et al.,7) this association was not replicated. Finally, the GϪ1470C polymorphism, recently identified in a Chinese population, was also shown to influence IL-1b production as a component of a haplotype consisting ofThe present study was designed to examine the influence of IL-1b genotypes on the anti-inflammatory efficiency of glucocorticoids and its possible involvement in mechanisms of glucocorticoid-resistance. Specifically, the effect of prednisolone on lipopolysaccharide (LPS)-stimulated IL-1b mRNA expression and protein release, and its association with IL-1b genotypes, were analyzed. Earlier we showed that multidrug resistance transporter 1 (MDR1/P-glycoprotein), encoded by the ABCB1 gene, which possibly effluxes glucocorticoids out of target cells, was down-regulated in its expression under inflammatory conditions in relation to the ABCB1 C3435T genotype.11) The effect of the C3435T polymorphism on IL-1b production was also examined. MATERIALS AND METHODSSubjects Human PBMC were obtained from 19 healthy Japanese volunteers (12 males and 7 females), ranging in age from 23 to 43 years old. The subjects took no medications and had no noteworthy health problems. Informed consent was obtained from all subjects prior to their participation in the study. The protocol was approved by the Institutional Review Board of Kobe University Hospital, Kobe University, Ja...

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Section: ϫ5contrasting

confidence: 83%

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confidence: 99%

IL-1.BETA. Genotype-Related Effect of Prednisolone on IL-1.BETA. Production in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

Markova

Nakamura

Makimoto

et al. 2007

Biological & Pharmaceutical Bulletin

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“…22) Sakaeda et al reported that 3435 T/T coding exon 26 produced higher MDR1 mRNA expression on duodenal specimen 22,23) and peripheral blood mononuclear cells stimulated by lipopolysaccharide. 24) These observations suggest that MDR1 polymorphisms for exon also participate the change in P-gp activity on BBB, though the clinical investigation for verapamil penetration into the brain 25) does not support this hypothesis. In the present study, we could not find any difference in 3435 CϾT polymorphism among the three subjects' groups.…”

Section: Discussionmentioning

confidence: 94%

MDR1 Gene Polymorphism in Japanese Patients with Schizophrenia and Mood Disorders Including Depression

Qian

Homma

Itagaki

et al. 2006

Biological & Pharmaceutical Bulletin

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Schizophrenia and depression has been reported to be associated with abnormal response of hypothalamus-pituitaryadrenal (HPA) system. [1][2][3][4][5] Dexamethasone suppression test (DST) has been used to assess the response of HPA system in several psychiatric disorders, [1][2][3][4][5][6] where suppression of plasma ACTH and cortisol via negative feedback was sometimes impaired. 6) Although the mechanisms for non-suppression of cortisol in DST has remained unclear, it has been suggested that pharmacokinetic alteration of dexamethasone was involved in non-suppressive patients with psychiatric disorders. 7,8) Penetration of dexamethasone into the brain is regulated by the blood-brain barrier (BBB) expressing P-gp (ABCB1-type P-gp), 9) multi-drug resistant (MDR1) gene encoding efflux pump, which protect the brain from several drugs. 10)Since P-gp is also known to be expressed on kidney, liver and intestine, 11) it is evident that phramacokinetic disposition of dexamethasone may be altered by P-gp activity. Muller et al. reported that mdr1 knockout mice enhanced dexamethasone sensitivity leading greater corticosterone suppression.12) This observation suggests that glucocorticoid response in DST is modified by P-gp expression on BBB, which is associated with MDR1 polymorphism. Higher expression of P-gp on BBB may produce poor access of dexamethasone to brain resulting in poor suppression of plasma cortisol levels, which is commonly observed in psychiatric disorders.Thus, P-gp as a neuroprotective barrier is likely to exert a influence on the pharmacodynamics of dexamethasone via BBB permeability, 12) as well as the etiology and pathogenesis of central nervous diseases such as Parkinson's disease. [13][14][15] We, therefore, investigated the single nucleotide polymorphisms (SNPs) on the MDR1 gene in patients with schizophrenia and mood disorders including depression, of which substantial population showed poor response to dexamethasone. SUBJECTS AND METHODSubjects were recruited in our hospital, Tsukuba university hospital in Japan. The diagnosis of schizophrenia (nϭ121) and mood disorders (nϭ62) was conducted according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV; American Psychiatric Association 1994). Subtype of each psychiatric disorder was indicated in Table 1. The control subjects (nϭ160) were patients receiving surgical operation (mastectomy, leg surgery and kidney transplantation), who had no present or past history of major psychiatric disorder including schizophrenia and mood disorders. Written informed consent was obtained from each participant. Blood samples were obtained from patients with schizophrenia, mood disorders and controls. The study was approved by the Ethical committee of University of Tsukuba. There was no different in age among the patients with schizophrenia and mood disorders, and the controls. P-Glycoprotein (ABCB1-type P-gp), a membrane protein encoded by the multi drug resistant gene (MDR1), expressing on the blood brain barrier protects the brain fro...

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“…The contradictory results may indicate that SNPs of the ABCB1 gene should be analyzed according to complete haplotypes instead of individually. Several different studies have found the 3435C>T polymorphism to be associated with a change in the expression of P-gp [30,46], although in transfection studies of cells, no differences in either mRNA or protein levels are observed [47].…”

Section: Discussionmentioning

confidence: 97%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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Genotype-dependent Down-regulation of Gene Expression and Function of MDR1 in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

Cited by 18 publications

References 29 publications

IL-1.BETA. Genotype-Related Effect of Prednisolone on IL-1.BETA. Production in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

IL-1.BETA. Genotype-Related Effect of Prednisolone on IL-1.BETA. Production in Human Peripheral Blood Mononuclear Cells under Acute Inflammation

MDR1 Gene Polymorphism in Japanese Patients with Schizophrenia and Mood Disorders Including Depression

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

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