Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase.
CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.
Shaw
M K
MK
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Newton
R S
RS
Sliskovic
D R
DR
Roth
B D
BD
Ferguson
E
E
Krause
B R
BR
D000818:Animals; D000069059:Atorvastatin; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005347:Fibroblasts; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000494:pharmacology; D008113:Liver Neoplasms; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D017035:Pravastatin; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000096:biosynthesis; D013777:Tetrazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D009281:Naphthalenes; D011758:Pyrroles; D013261:Sterols; D013777:Tetrazoles; C065178:BMY 21950; D000077340:Fluvastatin; D008148:Lovastatin; D000069059:Atorvastatin; D017035:Pravastatin