Down-regulation of ABCB1 transporter by atorvastatin in a human hepatoma cell line and in human peripheral blood mononuclear cells

Rodrigues, Alice Cristina; Curi, Rui; Britto, Luiz Roberto Giorgetti de; Rebbechi, Ivanise M.M.; Hirata, Mario H.; Bertolami, Marcelo Chiara; Bernik, Márcia Martins Silveira; Dórea, Egı́dio Lima; Hirata, Rosário Dominguez Crespo

doi:10.1016/j.bbagen.2006.08.003

Cited by 33 publications

(29 citation statements)

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“…A 3-to 4-fold induction of the SLCO2B1 and ABC genes was observed 25% (+12, 216) 241% (233, 265) 214% (+2, 235) LDL baseline (mM) 3.3 (1.6-6.1) 3.3 (1.6-6.1) 3.4 (2.9-5.5) 3.3 (2.9-4.8) LDL change in during study (min, max) 27% (+6, 219) -65% (248, 278) 221% (+3, 258) HDL baseline (mM) 1.6 (0.8-1.9) 1.3 (1.0-1.9) 1.6 (1.1-1.7) 1.1 (0.8-1.9) HDL change % during study (min, max) 0% (+10, 221) 0% (+20, 240) 212% (+18, 231) (Hoffart et al, 2012). Similarly, other in vitro studies investigating the expression profile of these genes after atorvastatin exposure in human hepatoma cells demonstrated an upregulation of the expression of SLCO2B1 and ABCG2 (Rodrigues et al, 2009) and downregulation of the ABCB1 expression (Rodrigues et al, 2006). However, in these cell experiments, supraphysiologic concentrations of statins were used that cannot be achieved in humans (Bjorkhem-Bergman et al, 2011).…”

Section: Discussionmentioning

confidence: 98%

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Atorvastatin Treatment Induces Uptake and Efflux Transporters in Human Liver

et al. 2013

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The metabolism and disposition of statins are highly dependent on different cytochrome P450 enzymes, such as CYP3A4 and CYP2C9, as well as membrane transporters SLCO1B1, SLCO2B1, ABCB1, and ABCG2. Interindividual gene expression differences among these enzymes may explain part of the variability in tolerance and effect for statin treatment. The aim of the present study was to investigate the effect of statin treatment on these genes in human liver tissue. Levels of CYP3A4, CYP2C9, SLCO1B1, SLCO2B1, ABCB1, and ABCG2 mRNA in liver tissue from a previously performed clinical trial in 29 patients randomized to treatment with placebo, 80 mg/day of atorvastatin, or 20 mg/day of fluvastatin for 4 weeks were measured using quantitative polymerase chain reaction. Treatment with atorvastatin (n = 10), but not with fluvastatin (n = 10), resulted in 3-fold higher expression of SLCO2B1 compared with placebo-treated patients (n = 9) (P < 0.05). Atorvastatin increased the expression of both ABCB1 and ABCG2 by more than 2-fold (P < 0.05). No difference was found in CYP2C9, CYP3A4, or SLCO1B1 mRNA expression in patients administered statins or those administered placebo. Premenopausal women (n = 8) had higher expression of CYP3A4 (P < 0.05) and lower expression of CYP2C9 (P < 0.05) compared with postmenopausal women (n = 10) and men (n = 11), respectively. Here we show for the first time that atorvastatin treatment leads to increased expression of the membrane transporters SLCO2B1, ABCB1, and ABCG2 in human liver tissue, which potentially may counteract the efficacy of the treatment, and our findings may cast light on the mechanisms of clinical problems with adverse reactions and drug interactions in statin treatment.

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Section: Discussionmentioning

confidence: 98%

“…Recent in vitro studies indicate that statins affect the gene expression of SLCOs and ABCs genes (Rodrigues et al, 2006(Rodrigues et al, , 2009Hoffart et al, 2012). However, the statins' impact on the expression of cytochromes, SLCOs, and ABCs in human liver tissues has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Treatment Induces Uptake and Efflux Transporters in Human Liver

et al. 2013

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“…HepG2 cells were treated with atorvastatin (kindly provided by Pfizer Pharmaceuticals Ltd., NY, USA), simvastatin (Sigma-Aldich), as previously reported [24,25], or ezetimibe (kindly provided by Merck/Schering-Plough, NJ, USA). Briefly, atorvastatin and ezetimibe were dissolved in methanol or ethanol respectively, while simvastatin was dissolved in ethanol and activated as described by Sadeghi et al [26].…”

Section: Methodsmentioning

confidence: 99%

Effects of Lipid-Lowering Drugs on Reverse Cholesterol Transport Gene Expressions in Peripheral Blood Mononuclear and Hepg2 Cells

et al. 2010

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Aims:The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that play an important role in reverse cholesterol transport. We examined the effects of inhibitors of the cholesterol absorption (ezetimibe) and synthesis (statins) on expression of these transporters in HepG2 cells and peripheral blood mononuclear cells (PBMCs) of individuals with primary (and nonfamilial) hypercholesterolemia (HC). Materials & methods:A total of 48 HC individuals were treated with atorvastatin (10 mg/day/4 weeks) and 23 were treated with ezetimibe (10 mg/day/4 weeks), followed by simvastatin (10 mg/day/8 weeks) and simvastatin plus ezetimibe (10 mg of each/day/4 weeks). Gene expression was examined in statin-or ezetimibe-treated and control HepG2 cells as well as PBMCs using real-time PCR. Results: In PBMCs, statins and ezetimibe downregulated ABCA1 and ABCG1 mRNA expression but did not modulate NR1H2 (LXR-b) and NR1H3 (LXR-a) levels. Positive correlations of ABCA1 with ABCG1 and of NR1H2 with NR1H3 expressions were found in all phases of the treatments. In HepG2 cells, ABCA1 mRNA levels remained unaltered while ABCG1 expression was increased by statin (1.0-10.0 µM) or ezetimibe (5.0 µM) treatments. Atorvastatin upregulated NR1H2 and NR1H3 only at 10.0 µM, meanwhile ezetimibe (1.0-5.0 µM) downregulated NR1H2 but did not change NR1H3 expression. Conclusion: Our findings reveal that lipid-lowering drugs downregulate ABCA1 and ABCG1 mRNA expression in PBMCs of HC individuals and exhibit differential effects on HepG2 cells. Moreover, they indicate that the ABCA1 and ABCG1 transcript levels were not correlated directly to LXR mRNA expression in both cell models treated with lipid-lowering drugs.KEYWORDS: ABCA1 n ABCG1 n ezetimibe n mRNA expression n PBMC n statins

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“…It has been demonstrated that atorvastatin regulates gene expression in blood leukocytes before changes in the lipid profile are detectable in serum [21]. Recently, we have demonstrated that atorvastatin inhibits ABCB1 (ATP-binding cassette B1) expression in blood mononuclear cells from hypercholesterolemic individuals with hypercholesterolemia and in HepG2 cells [22]. Moreover, freshly isolated blood mononuclear cells have been used as a surrogate for the cardiovascular tissue to study the correlation between gene expression and atherosclerosis severity [23].…”

Section: Introductionmentioning

confidence: 99%