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Abstract Background Berberine (BBR) is always used in combination with florfenicol for treating avian in China. Objective This study aims to investigate the effects of BBR on the pharmacokinetics of florfenicol in broilers. Methods Male broilers were randomly divided into the control group and the BBR group (BG). Note that 50 mg/kg BBR or sterile water was orally administrated to broilers. On the 8th day, florfenicol [30 mg/kg body weight (BW)] was orally administered to broilers in both groups. The plasma concentrations of florfenicol were determined by ultra‐high‐performance liquid chromatography (UHPLC). The levels of cytochrome P450 (CYP) 3A37, multidrug resistance 1 (MDR1), and chicken xenobiotic‐sensing orphan nuclear receptor (CXR) mRNA expression in the liver and jejunum were determined by the real‐time PCR. Results The results showed that the Cmax, t1/2z, MRT(0‐∞), and AUC(0‐∞) of florfenicol in BG were significantly increased (by 55.71%, 28.32%, 35.19%, and 55.62%, respectively), while the Tmax and CLz/F of florfenicol were significantly decreased (by 52.13% and 35.82%, respectively). In BG, the levels of CYP3A37, MDR1, and CXR mRNA expression in the liver were significantly decreased to 0.72‐fold, 0.67‐fold, and 0.59‐fold, respectively, and the corresponding mRNA expression in the jejunum were significantly decreased to 0.66‐fold, 0.55‐fold, and 0.64‐fold levels, respectively, relative to their levels in the control group. Conclusions BBR altered the pharmacokinetics of florfenicol, probably related to its inhibition of CYP3A37, MDR1, and CXR mRNA expression in the jejunum and liver.

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Background: Berberine (BBR) is always used in combination with florfenicol for treating avian in China. Objective: This study aims to investigate the effects of BBR on the pharmacokinetics of florfenicol in broilers. Methods: Male broilers were randomly divided into the control group and the BBR group (BG). Note that 50 mg/kg BBR or sterile water was orally administrated to broilers. On the 8th day, florfenicol [30 mg/kg body weight (BW)] was orally administered to broilers in both groups. The plasma concentrations of florfenicol were determined by ultra‐high‐performance liquid chromatography (UHPLC). The levels of cytochrome P450 (CYP) 3A37, multidrug resistance 1 (MDR1), and chicken xenobiotic‐sensing orphan nuclear receptor (CXR) mRNA expression in the liver and jejunum were determined by the real‐time PCR. Results: The results showed that the Cmax, t1/2z, MRT(0‐∞), and AUC(0‐∞) of florfenicol in BG were significantly increased (by 55.71%, 28.32%, 35.19%, and 55.62%, respectively), while the Tmax and CLz/F of florfenicol were significantly decreased (by 52.13% and 35.82%, respectively). In BG, the levels of CYP3A37, MDR1, and CXR mRNA expression in the liver were significantly decreased to 0.72‐fold, 0.67‐fold, and 0.59‐fold, respectively, and the corresponding mRNA expression in the jejunum were significantly decreased to 0.66‐fold, 0.55‐fold, and 0.64‐fold levels, respectively, relative to their levels in the control group. Conclusions: BBR altered the pharmacokinetics of florfenicol, probably related to its inhibition of CYP3A37, MDR1, and CXR mRNA expression in the jejunum and liver. [ABSTRACT FROM AUTHOR]

Previous researches exploring associations between multiple myeloma (MM) and genetic polymorphisms showed controversial results. In this investigation, we aimed to make a meta-analysis to assess the association between MM risk and genetic polymorphisms. We searched for articles on genetic polymorphism and MM risk in Web of Science and PubMed databases from 1951 to August 2019. We computed the odds ratio (OR) and 95% confidence intervals (CI) extracted from included articles. The meta-analysis showed no significant associations between MM risks and tumor necrosis factor (TNF)-α (rs1800629/rs361525/rs1799724), interleukin (IL)-6 (rs1800795), multidrug resistance 1 (MDR1) (rs1045642), Methylenetetrahydrofolate reductase (MTHFR) (rs1801131/rs1801133) polymorphisms. In summary, the study shows that the TNF-α (rs1800629/rs361525/rs1799724), IL-6 (rs1800795), MDR1 (rs1045642), and MTHFR (rs1801131/rs1801133) polymorphisms may not be associated with MM susceptibility. Thus, we do not need more expensive and useless studies to explore the associations between MM risks and these genetic polymorphisms. [ABSTRACT FROM AUTHOR]

Introduction: Several studies have evaluated the association between the multidrug resistance 1 (MDR1) polymorphism (rs1045642 C > T) and multiple myeloma (MM). However, the results were not consistent. Therefore, to reach a comprehensive and reliable answer we determined the association of the MDR1 (rs1045642 C > T) polymorphism and MM in the context of meta-analysis. Methods: All eligible studies published in EMBASE, PubMed, and Web of Science databases before July 2017 were reviewed. Subsequently, to assess the strength of association in the dominant model, recessive model, allelic model, homozygotes contrast, and heterozygotes contrast, pooled odds ratios and 95% confidence intervals (CIs) were calculated by the fixed effects model. Results: A total of four case-control studies with 395 MM cases and 418 healthy controls were included in the meta-analysis. The overall results showed no significant association between the MDR1 (rs1045642 C > T) polymorphism and the risk of MM in genetic models (dominant model: OR = 1.04, 95% CI = 0.78-1.38; recessive model: OR = 0.74, 95% CI = 0.52-1.06; allelic model: OR = 0.90, 95% CI = 0.73-1.11; TT vs. CC: OR = 0.80, 95% CI = 0.51-1.25; and CT vs. CC: OR = 1.12, 95% CI = 0.77-1.62). No evidence of publication bias was detected except for the analysis of the recessive model. Conclusion: This meta-analysis suggests that the MDR1 C > T polymorphism was not associated with the risk of MM. To confirm these findings, further comprehensive and well-designed studies are needed. [ABSTRACT FROM AUTHOR]

Lung cancer, with the highest morbidity and second highest death rates, is one of the most common cancers in both males and females worldwide. Lung adenocarcinoma (LAD) is the main lung cancer class. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) gene is an lncRNA which had been reported high-expression in colorectal cancer. In this study, the expression of KCNQ1OT1 was confirmed to be highly expressed in LAD tissues and cells contrast to control tissues and cells, and high KCNQ1OT1 expression correlated to malignant behaviors of LAD, including big tumor size, poor differentiation, positive lymphatic metastasis and high TNM stages. The transfection of si-KCNQ1OT1 could effectually knockdown the expression of KCNQ1OT1 in A549 and A549/PA cells. The KCNQ1OT1 knockdown depressed the proliferation and invasion of A549 cells, and advanced cellular apoptosis of A549 cells. The expression of KCNQ1OT1 in LAD patients insensitive to paclitaxel was much higher than that in LAD patients sensitive to paclitaxel; the KCNQ1OT1 expression in A549/PA cells was also much higher than that in control A549 cells. The half maximal inhibitory concentration (IC50) of paclitaxel in A549/PA cells was depressed by KCNQ1OT1 knockdown, chemoresistance of A549/PA cells was inhibited significantly. KCNQ1OT1 knockdown also depressed the expression of multidrug resistance 1 (MDR1) protein in A549/PA cells. In summary, lncRNA KCNQ1OT1 was highly expressed in LAD and functioned as a potential oncogene to inhibit malignancy and chemoresistance of LAD cells, which might be a novel potential therapeutic target for LAD. [ABSTRACT FROM AUTHOR]

Ｏｂｊｅｃｔｉｖｅ　Ｔｏ ｏｂｓｅｒｖｅ ｔｈｅ ｅｆｆｅｃｔｓ ｏｆ ｅｔｈｙｌ ａｃｅｔａｔｅ ｅｘｔｒａｃｔｓ ｏｆ Ｓｑｕｉｌｌａ ｏｒａｔｏｒｉａ （ＥＳＯ）ｏｎ ｐｒｏｌｉｆｅｒａｔｉｏｎ ａｎｄ ｄｒｕｇ ｒｅｓｉｓｔａｎｃｅ ｏｆ ｈｕｍａｎ ｌｕｎｇ ａｄｅｎｏｃａｒｃｉｎｏｍａ ｄｒｕｇｒｅｓｉｓｔａｎｔ ｃｅｌｌ ｌｉｎｅ Ａ５４９ ／ ＤＤＰ ａｎｄ ｔｏ ｉｎｖｅｓｔｉｇａｔｅ ｉｔｓ ｍｅｃｈａｎｉｓｍ． Ｍｅｔｈ ｏｄｓ 　Ｗｅ ｓｅｌｅｃｔｅｄ ｔｈｅ Ａ５４９ ／ ＤＤＰ ｃｅｌｌ ｌｉｎｅ，ｗｈｉｃｈ ｗｅｒｅ ｔｒｅａｔｅｄ ｗｉｔｈ ｄｉｆｆｅｒｅｎｔ ｃｏｎｃｅｎｔｒａｔｉｏｎｓ ｏｆ ＥＳＯ （０，２００，４００，８００ μｇ／ ｍｌ）ｆｏｒ ２４ ｈ． Ｔｈｅ ｐｒｏｌｉｆｅｒａｔｉｏｎ ｉｎｈｉｂｉｔｉｏｎ ｒａｔｅｓ ｏｆ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ ｗｅｒｅ ｄｅｔｅｃｔｅｄ ｂｙ ＭＴＴ ａｓｓａｙ． Ｔｈｅ ｃｅｌｌ ｃｙｃｌｅ ｐｅｒｃｅｎｔ ａｇｅ ｗａｓ ｄｅｔｅｒｍｉｎｅｄ ｂｙ ｆｌｏｗ ｃｙｔｏｍｅｔｒｙ （ＦＣＭ）． Ｗｅ ｕｓｅｄ ＦＣＭ ｔｏ ｄｅｔｅｃｔ ｔｈｅ Ｒｈｏｄａｍｉｎｅ１２３ （Ｒｈ１２３）ａｃｃｕｍｕｌａｔｉｏｎ ａｎｄ ｅｆ ｆｌｕｘ ｉｎ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ ｔｒｅａｔｅｄ ｗｉｔｈ ４００ μｇ／ ｍＬ ＥＳＯ ｆｏｒ ０，３０，ａｎｄ ６０ ｍｉｎ． Ａｆｔｅｒ ｔｈｅ ｃｅｌｌｓ ｗｅｒｅ ｔｒｅａｔｅｄ ｗｉｔｈ ｄｉｆｆｅｒｅｎｔ ｃｏｎｃｅｎｔｒａｔｉｏｎｓ ｏｆ ＥＳＯ ｆｏｒ ２４ ｈ，ｔｈｅ ｍｕｌｔｉｄｒｕｇ ｒｅｓｉｓｔａｎｃｅ １ （ＭＤＲ１）ｐｒｏｔｅｉｎ ｗａｓ ｄｅｔｅｃｔｅｄ ｂｙ Ｗｅｓｔｅｒｎ ｂｌｏｔｔｉｎｇ． Ｍｅａｎｗｈｉｌｅ， ｗｅ ｄｅｔｅｃｔｅｄ ｔｈｅ ＥＲＫ１ ／２，ｐＥＲＫ１ ／２ ｐｒｏｔｅｉｎ ｏｆ ｃｅｌｌｓ ａｆｔｅｒ ４００ μｇ／ ｍＬ ＥＳＯ ｔｒｅａｔｍｅｎｔ ｆｏｒ ２，４，ａｎｄ ８ ｈ． Ｒｅｓｕｌｔｓ　Ｔｈｅ ｐｒｏ ｌｉｆｅｒａｔｉｏｎ ｉｎｈｉｂｉｔｉｏｎ ｒａｔｅｓ ｏｆ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ ｔｒｅａｔｅｄ ｗｉｔｈ ２００，４００，ａｎｄ ８００ μｇ／ ｍＬ ＥＳＯ ｗｅｒｅ １９.９４０％ ± ０.０４１％ ， ３７.３６０％ ±０.０２４％ ，ａｎｄ ４２.５１０％ ±０.００８％ ，ａｎｄ ｓｉｇｎｉｆｉｃａｎｔ ｄｉｆｆｅｒｅｎｃｅ ｗａｓ ｆｏｕｎｄ ｂｅｔｗｅｅｎ ｅｖｅｒｙ ｔｗｏ ｇｒｏｕｐｓ （ａｌｌ Ｐ ＜ ０.０１）. Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ ｔｒｅａｔｅｄ ｗｉｔｈ ０，２００，４００，ａｎｄ ８００ μｇ／ ｍＬ ＥＳＯ ｃｏｕｌｄ ｂｅ ｂｌｏｃｋｅｄ ｉｎ Ｇ２ ／ Ｍ ｐｈａｓｅ，ａｎｄ ｔｈｅ ｐｒｏｌｉｆ ｅｒａｔｉｏｎ ｉｎｈｉｂｉｔｉｏｎ ｒａｔｅｓ ｗｅｒｅ ２４.０６％ ±２.２２％ ，３１.１％ ± ０.７９％ ，３５.６４％ ± １.１５％ ，ａｎｄ ４３.１９％ ± ０.４３％ ，ｒｅｓｐｅｃ ｔｉｖｅｌｙ；ｓｉｇｎｉｆｉｃａｎｔ ｄｉｆｆｅｒｅｎｃｅ ｗａｓ ｆｏｕｎｄ ｂｅｔｗｅｅｎ ｅｖｅｒｙ ｔｗｏ ｇｒｏｕｐｓ （ａｌｌ Ｐ ＜ ０.０１）. ＥＳＯ ｉｎｃｒｅａｓｅｄ ｔｈｅ ａｃｃｕｍｕｌａｔｉｏｎ ｏｆ Ｒｈ１２３ ｌｅｖｅｌ ｏｆ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ，ｒｅｄｕｃｅｄ ｔｈｅ ｅｆｆｌｕｘ，ａｎｄ ｔｈｉｓ ｃｈａｎｇｅ ｗａｓ ｍｏｒｅ ｓｉｇｎｉｆｉｃａｎｔ ａｔ ６０ ｍｉｎ ｔｈａｎ ａｔ ３０ ｍｉｎ （ａｌｌ Ｐ ＜０.０１）． Ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ ＭＲ１ ｐｒｏｔｅｉｎ ｗａｓ １.２２ ±０.２３，０.８３ ± ０．１６，０.３７ ± ０.０９，ａｎｄ ０.３１ ± ０.０４ ｉｎ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ ａｆｔｅｒ ０，２００，４００，８００ μｇ／ ｍＬ ｏｆ ＥＳＯ ｔｒｅａｔｍｅｎｔ ｒｅｓｐｅｃｔｉｖｅｌｙ，ａｌｌ Ｐ ＜０.０１． Ｈｏｗｅｖｅｒ，ｐＥＲＫ１ ／２ ｐｒｏｔｅｉｎ ｅｘｐｒｅｓｓｉｏｎ ｗａｓ ｕｐｒｅｇｕｌａｔｅｄ ｉｎ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ （Ｐ ＜ ０.０１），ｂｕｔ ｐＥＲＫ１ ／２ ｐｒｏｔｅｉｎ ｅｘｐｒｅｓｓｉｏｎ ｈａｄ ｎｏ ｖａｒｉａｔｉｏｎ ａｔ ｄｉｆｆｅｒｅｎｔ ｔｉｍｅ ｏｆ ＥＳＯ ｔｒｅａｔｍｅｎｔ． Ｃｏｎｃｌｕｓｉｏｎ　ＥＳＯ ｉｎｈｉｂｉｔｓ ｔｈｅ ｐｒｏｌｉｆｅｒａｔｉｏｎ ｏｆ Ａ５４９ ／ ＤＤＰ ｃｅｌｌｓ ｔｈｒｏｕｇｈ ｃｅｌｌ ｃｙｃｌｅ ａｒｒｅｓｔ，ａｎｄ ｒｅｖｅｒｓｅｓ ｔｈｅ ｍｕｌｔｉｄｒｕｇ ｒｅｓｉｓｔａｎｃｅ ｂｙ ｒｅｇｕｌａｔｉｎｇ ｔｈｅ ＭＡＰＫＥＲＫ１ ／２ ｓｉｇｎａｌｉｎｇ ｐａｔｈｗａｙ． [ABSTRACT FROM AUTHOR]

Abstract: Aims: The steroid and xenobiotic receptor (SXR) regulates the transcription of its target genes by interacting with various nuclear receptor cofactors. We have previously shown that silencing mediator for retinoid and thyroid receptors (SMRT) interacts with SXR even in the presence of rifampicin on cytochrome P450 monooxygenase 3A4 (CYP3A4) promoter in HepG2 cells. To examine the specificity of such interaction, the involvement of SMRT on SXR-mediated transcription through multidrug resistance (MDR) 1 gene promoter was examined using LS174T intestine-derived clonal cells. Main methods: Transient transfection-based reporter gene assay was carried out to examine the effect of SMRT or nuclear receptor corepressor (NCoR) on SXR-mediated transcription in LS174T cells. Semi-quantitative RT-PCR was performed to confirm the expression of MDR1 mRNA in LS174T cells. To examine the interaction of SMRT with SXR, we carried out mammalian one-hybrid assay in CV-1 cells and immunoprecipitation study in HEK-293 cells. Key findings: SMRT, but not NCoR suppressed rifampicin-induced SXR-mediated transcription. The SXR-mediated MDR1 mRNA expression was augmented in the presence of rifampicin, whereas it suppressed the expression following the overexpression of SMRT. In mammalian one-hybrid assay, only SMRT but not NCoR interacted with SXR on MDR1 promoter in the presence of rifampicin. In immunoprecipitation study, SMRT bound to SXR regardless of the presence or absence of rifampicin. Significance: SMRT may be recruited in the SXR-cofactor complex even in the presence of ligand. SMRT may be involved not only in SXR-mediated suppression without ligand, but also in ligand-activated transcription to suppress the overactivation of transcription. [Copyright &y& Elsevier]

Intestinal P-glycoprotein (Pgp/multidrug resistance 1), encoded by the ATP-binding cassette B1 gene, is primarily involved in the transepithelial efflux of toxic metabolites and xenobiotics from the mucosa into the gut lumen. Reduced Pgp function and expression has been shown to be associated with intestinal inflammatory disorders. Keratinocyte growth factor-2 (KGF2) has emerged as a potential target for modulation of intestinal inflammation and maintenance of gut mucosal integrity. Whether KGF2 directly regulates Pgp in the human intestine is not known. Therefore, the present studies were undertaken to determine the modulation of Pgp by KGF2 using Caco-2 cells. Short-term treatment of Caco-2 cells with KGF2 (10 ng/ml, 1 h) increased Pgp activity (~2-fold, P < 0.05) as measured by verapamil-sensitive [(3)H]digoxin flux. This increase in Pgp function was associated with an increase in surface Pgp levels. The specific fibroblast growth factor receptor (FGFR) antagonist PD-161570 blocked the KGF2-mediated increase in Pgp activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD-98059 attenuated the stimulatory effects of KGF2 on Pgp activity. Small-interfering RNA knockdown of Erk1/2 MAPK blocked the increase in surface Pgp levels by KGF2. Long-term treatment with KGF2 (10 ng/ml, 24 h) also significantly increased PgP activity, mRNA, protein expression, and promoter activity. The long-term effects of KGF2 on Pgp promoter activity were also blocked by the FGFR antagonist and mediated by the Erk1/2 MAPK pathway. In conclusion, our findings define the posttranslational and transcriptional mechanisms underlying stimulation of Pgp function and expression by KGF2 that may contribute to the beneficial effects of KGF2 in intestinal inflammatory disorders. [ABSTRACT FROM AUTHOR]

Aim ABCB1/MDR1 protein is found in high concentrations on the apical surfaces of colonic epithelial cells. It acts as an efflux pump by transporting toxic endogenous substances, drugs and xenobiotics out of cells. Polymorphisms in the ABCB1/ MDR1 gene may either change expression of the ABCB1/MDR1 protein or alter its function, suggesting its possible association with colorectal cancer. Several studies have reported a relationship between ABCB1 gene polymorphisms and colorectal cancer risk, but no consistent conclusion has been reached. We therefore conducted a meta-analysis to identify any association between the ABCB1 gene and CRC risk. Method PubMed, Embase, Google Scholar, Cbmdisc and CNKI were searched for studies on the relationship of ABCB1/MDR1 gene SNPs and the incidence of colorectal cancer. Eligible articles were included for data extraction. The main outcome was the frequency of ABCB1/MDR1 gene SNPs among cases and controls. Comparison of the distribution of SNPs was performed mainly using Review Manager 5.0. Results Ten, four and two trials were identified that focussed on the ABCB1 gene SNPs rs1045642, rs2032582 and rs3789243, respectively. A total of 3175 cases and 3715 controls were included. The meta-analysis, stratified by ethnicity or population source, indicated no association between the ABCB1 gene rs1045642 polymorphism and colorectal cancer risk. However, when the study by Bae et al. was removed from the analysis, there was some evidence to indicate a higher T-allele frequency in Asian colorectal cancer patients (OR = 1.30, 95% CI: 1.02-1.67, P = 0.03). Neither ABCB1 rs2032582 nor ABCB1 rs3789243 indicated an association with colorectal cancer risk. An increased frequency only of the wild-type combined allele (rs2032582G/rs1045642C) was found in Caucasian patients (OR = 1.22, 95% CI: 1.03-1.44, P = 0.02). Conclusion There is some evidence to indicate an association between ABCB1 rs1045642T and colorectal cancer risk in Asians. Compared with the ABCB1 gene SNPs rs1045642, rs2032582 or rs3789243 alone, combined haplotypes of several SNPs might be a better marker to determine the genetic influence on the susceptibility to colorectal cancer among Caucasians. [ABSTRACT FROM AUTHOR]

Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular 'xenosensors' like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2 and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the four genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European case-control study (EpiLymph) using the Illumina GoldenGate™ assay technology. Carriers of the SNP rs6857600 minor allele in ABCG2 was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall ( p < 0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant ( p = 0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL. [ABSTRACT FROM AUTHOR]

Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO-resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) mediates efflux of xenobiotics and bacterial toxins from the intestinal mucosa into the lumen. Dysregulation of P-gp has been implicated in inflammatory bowel disease. Certain probiotics have been shown to be effective in treating inflammatory bowel disease. However, direct effects of probiotics on P-gp are not known. Current studies examined the effects of Lactobacilli on P-gp function and expression in intestinal epithelial cells. Caco-2 monolayers and a mouse model of dextran sulfate sodium-induced colitis were utilized. P-gp activity was measured as verapamil-sensitive [3H]digoxin transepithelial flux. Multidrug resistant 1 (MDR1)/P-gp expression was measured by real-time quantitative PCR and immunoblotting. Culture supernatant (CS; 1:10 or 1:50, 24 h) of Lactobacillus acidophilus or Lactobacillus rhamnosus treatment of differentiated Caco-2 monolayers (21 days postplating) increased (~3-fold) MDR1/P-gp mRNA and protein levels. L. acidophilus or L. rhamnosus CS stimulated P-gp activity (~2-fold, P < 0.05) via phosphoinositide 3-kinase and ERK1/2 MAPK pathways. In mice, L. acidophilus or L. rhamnosus treatment (3 × 109 colony-forming units) increased mdr1a/P-gp mRNA and protein expression in the ileum and colon (2- to 3-fold). In the dextran sulfate sodium (DSS)-induced colitis model (3% DSS in drinking water for 7 days), the degree of colitis as judged by histological damage and myeloperoxidase activity was reduced by L. acidophilus. L. acidophilus treatment to DSS-treated mice blocked the reduced expression of mdr1a/P-gp mRNA and protein in the distal colon. These findings suggest that Lactobacilli or their soluble factors stimulate P-gp expression and function under normal and inflammatory conditions. These data provide insights into a novel mechanism involving P-gp upregulation in beneficial effects of probiotics in intestinal inflammatory disorders. [ABSTRACT FROM AUTHOR]

ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood-brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood-brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD).Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S-CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8.The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety.Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD. [ABSTRACT FROM AUTHOR]

Abstract: P-glycoprotein (P-gp), the product of the MDR1 gene, shows large interindividual variations in expression, which leads to differences in the pharmacokinetics of the substrate drugs. The functions of single nucleotide polymorphisms located in the nuclear receptor-responsive element of the 5′-flanking region in the human MDR1 gene were analyzed in order to clarify the mechanism underlying the interindividual variation in P-gp expression. Electrophoretic mobility shift assays revealed that the −7833C>T substitution in the nuclear receptor-responsive region of MDR1 decreases the binding affinities of four nuclear receptors to their responsive elements: vitamin D receptor (VDR), thyroid hormone receptor (TR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). A reporter gene assay revealed that the C-to-T substitution at −7833 also reduces the transcriptional activation of MDR1 by VDR, TRβ, CAR, and PXR. However, another SNP (−1211T>C substitution), which results in the formation of a xenobiotic responsive element-like sequence and a hypoxia responsive element-like sequence, failed to affect the aryl hydrocarbon receptor-dependent and hypoxia-induced transcriptional activation of MDR1. Although the frequency of the −7833C>T substitution in MDR1 is relatively low, the SNP is crucial because it may alter the pharmacokinetics of P-gp substrates in a small subset of the population. [ABSTRACT FROM AUTHOR]

Objective. Crohn's disease (CD) and ulcerative colitis (UC) are characterized by an impaired mucosal defence to normal constituents of the intestinal flora and a dysregulated inflammatory response. The purpose of the study was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in these processes were associated with CD and UC. Material and methods. Allele frequencies of the cyclooxygenase 2 (COX-2/PTGS2/PGHS2) G-765C and breast cancer resistance protein (BCRP/ABCG2) C421A as well as allele and haplotype frequencies of multidrug resistance 1 (MDR1, ABCB1) SNPs G2677T/A, C3435T and G-rs3789243-A (intron 3) were assessed in a Danish case-control study comprising 373 CD and 541 UC patients and 796 healthy controls. Results. Carriers of the homozygous COX-2 and MDR1 intron 3 variant had a relatively high risk of CD, odds ratio (95% CI) (OR (95% CI))=2.86 ((1.34-5.88) p=0.006) and 1.39 ((0.99-1.92) p=0.054), respectively, and for UC of 2.63 ((1.33-5.26) p=0.005) and 1.28 ((0.96-1.51) p=0.093), respectively, assuming complete dominance. No association was found for BCRP or other MDR1 SNPs, or for selected MDR1 haplotypes. No effect-modification of smoking habit at the time of diagnosis was found. Conclusions. An effect of the COX-2 polymorphism on both CD and UC was shown which is compatible with the presence of a recessive allele in linkage equilibrium with the SNP marker in the COX-2 gene. The polymorphism located in intron 3 of the MDR1 gene showed a weak association with CD, and a marginally suggestive association with UC. [ABSTRACT FROM AUTHOR]

Abstract: P-glycoprotein, encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter and plays an important role in pharmacokinetics. The expression of MDR1 is induced by a variety of compounds, of which 1α,25-dihydroxyvitamin D3 is known to be an effective inducer. However, it remains unclear how 1α,25-dihydroxyvitamin D3 regulates the expression of MDR1. In this study, we demonstrated that the vitamin D receptor (VDR) induces MDR1 expression in a 1α,25-dihydroxyvitamin D3-dependent manner. Luciferase assays revealed that the region between −7.9 and −7.8kbp upstream from the transcription start site of the MDR1 is responsible for the induction by 1α,25-dihydroxyvitamin D3. Electrophoretic mobility shift assays revealed that several binding sites for the VDR/retinoid X receptor α (RXRα) heterodimer are located between the −7880 and −7810bp region, to which the three molecules of VDR/RXRα are able to simultaneously bind with different affinities. Luciferase assays using mutated constructs revealed that the VDR-binding sites of DR3, DR4(I), MdC3, and DR4(III) contribute to the induction, indicating that these binding sites act as vitamin D response elements (VDREs). The contribution of each VDRE to the inducibility was different for each response element. An additive effect of the individual VDREs on induced luciferase activity by 1α,25-dihydroxyvitamin D3 was also observed. These results indicate that the induction of MDR1 by 1α,25-dihydroxyvitamin D3 is mediated by VDR/RXRα binding to several VDREs located between −7880 and −7810bp, in which every VDRE additively contributes to the 1α,25-dihydroxyvitamin D3 response. [Copyright &y& Elsevier]

Studies over the last decade have shown that Salmonella enterica serovar Typhimurium (S. lyphimurium) is able to preferentially locate to sites of tumor growth and modulate (shrink) the growth of many cancers. Given this unique association between S. lyphimurium and cancer cells, the objective of this study was to investigate the capacity of this microorganism to modulate the plasma membrane multidrug resistance (MDR) protein P-glycoprotein (P-gp), an ATP-binding cassette transporter responsible for effluxing many cancer drugs. Using an in vitro model of S. typhimurium infection of polarized human cancer intestinal cell lines, we have found that this enteric pathogen functionally downregulates the efflux capabilities of P-gp. Specifically, we show that S. typhimurium infection of human intestinal cancer cells results in the enhanced intracellular accumulation of a number of P-gp substrates that corresponds to the posttranscriptional downregulation of P-gp expression. Furthermore, cells expressing small interfering RNAs against MDR1, the gene encoding P-gp, were significantly more susceptible to the cytotoxic effects of bacterial infection. This result is consistent with our observation that S. typhimurium was significantly less able to invade cells overexpressing MDR1. Taken together, these results reveal a novel role for P-gp in the maintenance of homeostasis in the gastrointestinal tract in regard to bacterial infection. Thus the regulation of P-gp by S. typhimurium has important implications not only for the development of new cancer therapeutics aimed at reversing drug resistance but also in the understanding of how microbes have evolved diverse strategies to interact with their host. [ABSTRACT FROM AUTHOR]

The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype.Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5∗3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program.CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A5∗1 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17-1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A5∗3/∗3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan-Meier method, was significantly associated with the recipient's but not donor's CYP3A5 genotype (∗1/∗1 and ∗1/∗3 vs. ∗3/∗3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81).These findings suggest that the CYP3A5∗1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity. [ABSTRACT FROM AUTHOR]

Digoxin is a known substrate of ATP-binding cassette B1 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population.Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C→T, 2677G→T/A, and 3435C→T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders.Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18-0.21 μg/l per additional T allele). The association was even stronger for the 1236-2677-3435 TTT haplotype allele [0.26 μg/l (95% CI 0.14-0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects.We found that the common ABCB1 1236C→T, 2677G→T, and 3435C→T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population. [ABSTRACT FROM AUTHOR]

The multidrug resistance 1 (MDR1) gene product, P-glycoprotein (Pgp/p170) is a membrane protein, which acts as an ATP dependant efflux pump that expels a wide variety of organic compounds including chemotherapeutic agents from the cell. Pgp over expression has been demonstrated to be linked with poor treatment outcome and poor prognosis in a number of malignant tumors. AgNORs is a simple, reliable and inexpensive method of evaluating the proliferative activity of a tumor. We have studied MDR1 expression and AgNORS in 41 cases of acute leukemia in children. In this study, AgNOR counts in patients with acute lymphoblastic leukemia (ALL) L2 subtype (FAB classification) were significantly higher as compared to the ALL L1 subtype. Similarly, mean AgNOR count in the acute myeloid Leukemia (AML) M2 subtype was significantly higher as compared to the ALL L1 subtype. However, there was no correlation between AgNOR and treatment outcome or between AgNOR counts and MDR1 expression in any of the subtypes of acute leukemia included in this series. In AML, MDR1 gene expression was found to be related to reduced remission induction rates and hence poorer prognosis. In ALL, our study has shown no difference in remission induction between MDR1 positive and MDR1 negative cases. This would suggest that factors other than MDR1 may be of relevance in Pediatric ALL. [ABSTRACT FROM AUTHOR]

Previous murine studies have suggested that retroviral multidrug resistance 1 (MDR1) gene transfer may be associated with a myeloproliferative disorder. Analyses at a clonal level and prolonged long-term follow-up in a model with more direct relevance to human biology were lacking. In this study, we analyzed the contribution of individual CD34-selected peripheral blood progenitor cells to long-term rhesus macaque hematopoiesis after transduction with a retroviral vector either expressing the multidrug resistance 1 gene (HaMDR1 vector) or expressing the neomycin resistance (NeoR) gene (G1Na vector). We found a total of 122 contributing clones from 8 weeks up to 4 years after transplantation. One hundred two clones contained the G1Na vector, whereas only 20 clones contained the HaMDR1 vector. Here, we show for the first time realtime polymerase chain reaction based quantification of individual transduced cell clones constituting 0.0008% ± 0.0003% to 0.0041% ± 0.00032% of primate peripheral blood cells. No clonal dominance was observed. [ABSTRACT FROM AUTHOR]

Abstract: The cytochrome P450 3A (CYP3A) is a member of the cytochrome P450 monooxygenase superfamily. The multidrug resistance 1 (MDR1) gene belongs to the ATP-binding cassette (ABC) family. Pregnane X receptor (PXR) is a nuclear receptor that regulates its target gene transcription in a ligand-dependent manner. Lipopolysaccharide (LPS)-induced downregulation of PXR, CYP3A and MDR1 in liver has been demonstrated in a series of studies. However, it is not clear whether LPS represses the expression of PXR, CYP3A and MDR1 in placenta. In the present study, we investigated the effects of LPS on the expression of PXR, cyp3a11 and mdr1a in mouse placenta. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1–0.5mg/kg) on gestational day (gd) 17. Placental PXR, cyp3a11 and mdr1a mRNA levels were determined at 12h after LPS treatment using RT-PCR. Results showed that LPS significantly downregulated PXR, cyp3a11 and mdr1a mRNA levels in a dose-dependent manner. LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in placenta was significantly attenuated after pregnant mice were pre- and post-treated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiments revealed that LPS increased lipid peroxidation and proinflammatory cytokine expressions in mouse placenta, all of which were also attenuated by PBN. Furthermore, LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in mouse placenta was prevented by N-acetylcysteine (NAC). NAC also inhibited LPS-initiated lipid peroxidation, GSH depletion and proinflammatory cytokine expressions in mouse placenta. These results indicated that LPS downregulates placental PXR, cyp3a11 and mdr1a mRNA expressions. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR, cyp3a11 and mdr1a in mouse placenta. [Copyright &y& Elsevier]

Objective: Nasopharyngeal carcinoma (NPC) is one of the dominant cancers in South China and Taiwan. Although NPC is highly chemosensitive, the use of chemotherapy for treating patients with recurrent or metastatic NPC has not been very successful. The emergence of drug resistance may be one of the major reasons. However, the mechanisms of drug resistance of NPC have never been addressed before. In this study, we sought to clarify the role of classical drug resistance markers in predicting the chemosensitivity and the prognosis of patients with advanced NPC. Methods: In a cohort of 202 consecutive patients diagnosed at the Department of Pathology of the National Taiwan University Hospital, 44 patients with adequately preserved pretreatment tumor tissues and complete clinical information regarding the details of chemotherapy and tumor response were identified. The expression of multidrug resistance (MDR1), glutathione-S-transferase-π (GSTπ), and p53 were determined by immunohistochemistry. Tumor response to chemotherapy and survival of the patients were the endpoints of this analysis. Results: Thirty-four patients received cisplatin-based regimens, and 28 of them were enrolled in a prospective trial using a doxorubicin-containing regimen. The overall response rate was 70%. Expression of MDR1 was seen in only 5 cases (11%) and was associated with a significantly worse overall survival, yet did not appear to predict chemoresistance to the doxorubicin-containing regimen. Overexpression of p53 was seen in 22 patients, and surprisingly, was correlated with chemoresponse and a trend towards better survival. GSTπ expression was demonstrated in 13 cases (30%) and was not correlated with chemoresistance to cisplatin-containing regimens and overall survival. Conclusion: In this relatively small cohort, positive MDR1 immunostaining predicted a poor overall survival for recurrent or metastatic NPC patients receiving chemotherapy. Overexpression of p53 by immunohistochemical staining, however, was associated with a better response rate to systemic chemotherapy and a trend towards better survival.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]