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Dow‐regulation of ABCB1 transporter by atorvastatin in a human hepatoma cell line
Author(s) -
Rodrigues Alice Cristina,
Curi Rui,
Britto Luiz R.G.,
Rebbechi Ivanise M. M.,
Hirata Mario H.,
Hirata Rosario D.C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a486-b
Subject(s) - atorvastatin , multidrug resistance associated protein 2 , bone canaliculus , transporter , chemistry , efflux , messenger rna , atp binding cassette transporter , reductase , pharmacology , microbiology and biotechnology , medicine , biology , biochemistry , enzyme , gene
The effect of atorvastatin, an HMG‐CoA reductase inhibitor, on expression and activity of the drug transporter ABCB1 in HepG2 cells was examined. Immunohistochemical analysis revealed that ABCB1 is located at the apical membrane of the bile canaliculi. Atorvastatin at 10 and 20μM up‐regulated ABCB1 expression resulting in a 1.4‐fold increase of the protein levels (Fluorescence Intensity Mean ± SEM; n=4: control: 34 ± 2; 10μM: 47 ± 4; 20μM: 49 ± 5, p <0.05). HepG2 cells treated with 20μM atorvastatin showed a 50% reduction in mRNA expression by real‐time PCR and a 41% decrease in ABCB1‐mediated efflux of rhodamine123. A positive correlation was found between ABCB1 mRNA levels and ABCB1 activity (r=0.91; p <0.05). Our data suggest that high concentration of atorvastatin leads to decreased ABCB1 function and modulates ABCB1 synthesis in HepG2 cells. As ABCB1 appears to play a role in cellular protection as well as in secretion and/or disposition, thus, inhibition of ABCB1 synthesis may result in resistance to atorvastatin and may raise its plasma concentrations that may cause adverse effects. FAPESP.