Potential downregulation of HMG-CoA reductase after prolonged administration of P-407 in C57BL/6 mice.
This study investigated the potential alteration in the amount of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase messenger RNA (mRNA) and lipoprotein lipase (LPL) mRNA in the livers of C57BL/6 mice after long-term (200 days) treatment with the nonionic surfactant called poloxamer 407 (P-407). Previously, P-407 has been used to produce a dose-controlled hyperlipidemic state in C57BL/6 mice with subsequent formation of atherosclerotic lesions. Five groups of mice were studied; controls (C); mice fed a standard chow diet enriched with only cholic acid (CH); mice fed the high-cholesterol, high-fat Paigen diet (HF); mice treated with 0.5 g/kg P-407 every third day (P); and mice administered 0.5 g/kg P-407 every third day while consuming a diet identical to that of mice in group CH (PC). Neither a significant (p < 0.05) weight loss nor alteration in liver enzymes (AST and ALT) were observed for any group throughout the study when compared with the control mice. Total plasma cholesterol (CHOL) was significantly elevated compared with controls for mice in groups HF, P, and PC, whereas total plasma triglycerides (TG) were significantly increased for mice in only groups P and PC. Long-term ingestion of a high-fat diet or a diet enriched in cholic acid resulted in a significant (p < 0.05) reduction in HDL-CHOL when compared with controls. Plasma samples assayed at 200 days for mice in groups HF and P showed a shift in the lipoprotein fraction distribution primarily to VLDL-CHOL as compared with mice in group C in which, as expected, most of the CHOL was contained in the HDL fraction. The biologic activity of HMG-CoA reductase assayed in hepatic microsomal homogenates was significantly reduced for mice in groups CH (p < 0.01), HF (p < 0.01), and PC (p < 0.05), but not for mice in group P, when compared with control. A statistical analysis of the data demonstrated significant (p < 0.05) reductions in the HMG-CoA reductase mRNA levels in hepatic tissue for all treatment groups relative to mRNA levels determined for mice in group C. In contrast, no treatment group demonstrated a significant difference in hepatic LPL mRNA levels when compared with mRNA levels determined for control animals. These data demonstrate that P-407 administration to C57BL/6 mice significantly decreased the amount of HMG-CoA reductase mRNA detected in liver.
Johnston
T P
TP
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, Kansas City 64110-2499, USA. johnstont@umkc.edu
Baker
J C
JC
Jamal
A S
AS
Hall
D
D
Emeson
E E
EE
Palmer
W K
WK
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D006949:Hyperlipidemias / Q000188:drug therapy / Q000209:etiology; D008071:Lipoprotein Lipase / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020442:Poloxamer / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis; D013501:Surface-Active Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014280:Triglycerides / Q000097:blood
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D013501:Surface-Active Agents; D014280:Triglycerides; D020442:Poloxamer; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008071:Lipoprotein Lipase