title: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats.
abstract: OBJECTIVE
  Biliary cholesterol secretion is coupled to that of phospholipids in a process controlled by mdr2 P-glycoprotein activity and bile salt secretion. Statins, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been shown to affect hepatobiliary lipid secretion in rats. The aim of this study was to relate the effects of statins on bile formation to the expression of mdr2 and other hepatic adenosine triphosphate-dependent transport proteins involved in bile formation in rats.
  
  
  METHODS
  Rats received simvastatin- or pravastatin-containing chow continuously for 5 days. In one group of rats, simvastatin treatment was withdrawn 9-12 hours before the end of the experiment to induce biliary cholesterol hypersecretion (rebound). Bile and liver tissue were collected for lipid analysis, and hepatic messenger RNA (mRNA) and protein levels were studied by reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry.
  
  
  RESULTS
  Simvastatin feeding did not alter biliary bile salt secretion. Secretion of phospholipids and cholesterol was stimulated by 74% and 90%, respectively, in the simvastatin-continuous group and by 72% and 235%, respectively, in the rebound group compared with controls. mdr2 mRNA levels increased only in the continuous group. mdr2 protein levels increased in both simvastatin-fed groups. Induction was most pronounced in periportal hepatocytes. mdr1b mRNA levels were moderately increased in both simvastatin-fed groups. Levels of other hepatic transport proteins did not change. Similar results were obtained in pravastatin-fed rats.
  
  
  CONCLUSIONS
  Statins increase expression of mdr2 and mdr1b in rats, revealing a novel effect of these commonly used drugs.
authors.affiliation: Groningen Institute for Drug Studies, University of Groningen, Groningen, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Hooiveld
authors.forename: T A
authors.initials: TA
authors.lastname: Vos
authors.forename: G L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: H
authors.initials: H
authors.lastname: Van Goor
authors.forename: H
authors.initials: H
authors.lastname: Koning
authors.forename: V
authors.initials: V
authors.lastname: Bloks
authors.forename: A E
authors.initials: AE
authors.lastname: Loot
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
authors.forename: P L
authors.initials: PL
authors.lastname: Jansen
authors.forename: F
authors.initials: F
authors.lastname: Kuipers
authors.forename: M
authors.initials: M
authors.lastname: Müller
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism*; D015153:Blotting, Western; D002784:Cholesterol / Q000096:biosynthesis; D004144:Diosgenin / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010743:Phospholipids / Q000096:biosynthesis; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002784:Cholesterol; D004144:Diosgenin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010743:Phospholipids; D017035:Pravastatin; D012333:RNA, Messenger; D019821:Simvastatin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3