Acta Pharmacologica Sinica (2009) 30: 956-964; doi: 10.1038/aps.2009.85; published online 22 June 2009

Aim: 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 SLC 22A 1) 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>>>SLC 22A 1>SLCO2B1 for HepG2 cells, and SLCO2B1>>ABCC2>ABCB1>ABCG2>>>SLC 22A 1 for Caco-2 cells.  While for HepG2 cells, ABCC2, ABCG2 and SLCO2B1 mRNA levels were significantly up-regulated at 1, 10 and 20 µmol/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, SLC 22A 1, and SLCO2B1 mRNA levels after 12 or 24 h treatment. 

Conclusion: 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.

Keywords: simvastatin; atorvastatin; Caco-2 cells; HepG2 cells; drug transporters