title: Atorvastatin treatment induces uptake and efflux transporters in human liver.
abstract: 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.
authors.affiliation: Division of Clinical Pharmacology, Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. linda.bjorkhem-bergman@ki.se
authors.forename: Linda
authors.initials: L
authors.lastname: Björkhem-Bergman
authors.forename: Helena
authors.initials: H
authors.lastname: Bergström
authors.forename: Maria
authors.initials: M
authors.lastname: Johansson
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Mats
authors.initials: M
authors.lastname: Eriksson
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Lena
authors.initials: L
authors.lastname: Ekström
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use; D005260:Female; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D026901:Membrane Transport Proteins; D011758:Pyrroles; D012333:RNA, Messenger; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin