3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats

Background & Aims: Biliary cholesterol secretion is coupled to that of phos pholipids 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 secre tion 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 triph osphate-dependent transport proteins involved in bile formation in rats. Me thods: Rats received simvastatin-or pravastatin-containing chow continuousl y for 5 days. In one group of rats, simvastatin treatment was withdrawn 9-1 2 hours before the end of the experiment to induce biliary cholesterol hype rsecretion (rebound). Bile and liver tissue were collected for lipid analys is, and hepatic messenger RNA (mRNA) and protein levels were studied-by rev erse-transcription polymerase chain reaction, immunoblotting, and immunohis tochemistry. Results: Simvastatin feeding did not alter biliary bile salt s ecretion. Secretion of phospholipids,and cholesterol was stimulated by 74% and 90%, respectively, in the simvastatin-continuous group and by 72% and 2 35%, respectively, in the rebound group compared with controls. mdr2 mRNA l evels increased only in the continuous group. mdr2 protein levels increased in both simvastatin-fed groups. Induction was most pronounced in periporta l hepatocytes. mdr1b mRNA levels were moderately increased in both simvasta tin-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.