Effects of pravastatin and bezafibrate on biliary lipid excretion and hepatic expression of Abcg5 and Abcg8 in the rat.
OBJECTIVE
Multidrug resistance associated gene product 2 (Mdr2) is believed to have a significant role in biliary cholesterol and phospholipid secretions. Both pravastatin and bezafibrate resulted in Mdr2 induction, but increased cholesterol secretion was observed only in pravastatin treatment. To explore the mechanism, the hepatic expression of genes that are responsible for the metabolism of the lipids was studied.


METHODS
Rats were divided into three experimental groups: (i) the control group; (ii) the bezafibrate group, which was fed a diet containing 0.45% bezafibrate for 5 days; and (iii) the pravastatin group, which was fed a diet containing 0.1% pravastatin for 5 days. Serum, hepatic and biliary lipids were measured by colorimetric assays and hepatic mRNA related to lipid metabolism was studied by reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
In the bezafibrate group biliary phospholipid secretion was increased although cholesterol secretion was not increased. In the pravastatin group, biliary cholesterol and phospholipid secretions were significantly increased. The biliary cholesterol/phospholipid ratio was decreased in the bezafibrate group, but the ratio did not change in the pravastatin group. Hepatic Mdr2, Abcg5 and Abcg8 mRNA expression was remarkably increased in the pravastatin group in comparison with the control group (184%, 264% and 247% of control value, respectively). In the bezafibrate group the hepatic gene expression of Mdr2 was increased (157% of control value), but there were no significant changes in hepatic Abcg5 and Abcg8 mRNA expression compared with the control group.


CONCLUSIONS
Compared with Mdr2, Abcg5 and Abcg8 seem to be more essential transporters for biliary secretion of cholesterol. Pravastatin upregulated Abcg5/Abcg8 while bezafibrate did not, which appears to explain the different effects of these compounds on biliary lipid secretion.
Kamisako
Toshinori
T
Department of Hygiene, Kinki University School of Medicine, 377-2 Ohnohigashi, Osakasayama 589-8511, Japan. kamisako@med.kindai.ac.jp
Ogawa
Hiroshi
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018435:ATP Binding Cassette Transporter, Subfamily B; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; C480692:Abcg5 protein, rat; C480693:Abcg8 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D012333:RNA, Messenger; C095122:multidrug resistance protein 3; D017035:Pravastatin; D001629:Bezafibrate