RT Journal Article
SR Electronic
T1 Atorvastatin Treatment Induces Uptake and Efflux Transporters in Human Liver
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.113.051698
DO 10.1124/dmd.113.051698
A1 Linda Bjorkhem-Bergman
A1 Helena Bergstrom
A1 Maria Johansson
A1 Paolo Parini
A1 Mats Eriksson
A1 Anders Rane
A1 Lena Ekstrom
YR 2013
UL http://dmd.aspetjournals.org/content/early/2013/06/10/dmd.113.051698.abstract
AB 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. Inter-individual 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, atorvastatin 80 mg/d or fluvastatin 20mg/d for 4 weeks were measured using quantitative PCR. Atorvastatin treatment (n=10) but not fluvastatin (n=10), resulted in three-fold higher expression of SLCO2B1 compared to placebo-treated (n=9) (p<0.05). Atorvastatin, increased the expression of both ABCB1 and ABCG2 more than two-fold (p<0.05). There was no difference in CYP2C9, CYP3A4 or SLCO1B1 mRNA expression between patients administered statins or placebo. Premenopausal women (n=8) had higher expression of CYP3A4 (p<0.05) and lower expression of CYP2C9 (p<0.05) compared to 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. This may potentially counteract the efficacy of the treatment and our findings may cast light on mechanisms of clinical problems with adverse reactions and drug interactions in statin treatment.