The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells.
OBJECTIVE
Statin disposition and response are greatly determined by the activities of drug metabolizing enzymes and efflux/ uptake transporters. There is little information on the regulation of these proteins in human cells after statin therapy. In this study, the effects of atorvastatin and simvastatin on mRNA expression of efflux (ABCB1, ABCG2 and ABCC2) and uptake (SLCO1B1, SLCO2B1 and SLC22A1) drug transporters in Caco-2 and HepG2 cells were investigated.


METHODS
Quantitative real-time PCR was used to measure mRNA levels after exposure of HepG2 and Caco-2 cells to statins.


RESULTS
Differences in mRNA basal levels of the transporters were as follows: ABCC2>ABCG2>ABCB1>SLCO1B1>>>SLC22A1>SLC O2B1 for HepG2 cells, and SLCO2B1>>ABCC2>ABCB1>ABCG2>>>SLC22A1 for Caco-2 cells. While for HepG2 cells, ABCC2, ABCG2 and SLCO2B1 mRNA levels were significantly up-regulated at 1, 10 and 20 micromol/L after 12 or 24 h treatment, in Caco-2 cells, only the efflux transporter ABCB1 was significantly down-regulated by two-fold following a 12 h treatment with atorvastatin. Interestingly, whereas treatment with simvastatin had no effect on mRNA levels of the transporters in HepG2 cells, in Caco-2 cells the statin significantly down-regulated ABCB1, ABCC2, SLC22A1, and SLCO2B1 mRNA levels after 12 or 24 h treatment.


CONCLUSIONS
These findings reveal that statins exhibits differential effects on mRNA expression of drug transporters, and this effect depends on the cell type. Furthermore, alterations in the expression levels of drug transporters in the liver and/or intestine may contribute to the variability in oral disposition of statins.Acta Pharmacologica Sinica (2009) 30: 956-964; doi: 10.1038/aps.2009.85; published online 22 June 2009.
Rodrigues
Alice Cristina
AC
Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Av Prof Lineu Prestes, 580, Sao Paulo, SP, 05508-900, Brazil. alice-rodrigues@usp.br
Curi
Rui
R
Genvigir
Fabiana Dalla Vecchia
FD
Hirata
Mario Hiroyuki
MH
Hirata
Rosario Dominguez Crespo
RD
D000818:Animals; D000069059:Atorvastatin; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000378:metabolism / Q000494:pharmacology
C000715087:ABCC2 protein, human; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D011758:Pyrroles; D012333:RNA, Messenger; D000069059:Atorvastatin; D019821:Simvastatin