Lovastatin, an inhibitor of cholesterol synthesis, induces hydroxymethylglutaryl-coenzyme A reductase directly on membranes of expanded smooth endoplasmic reticulum in rat hepatocytes.
Lovastatin is a potent competitive inhibitor of the rate-limiting enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (NADPH) [HMG-CoA reductase; (S)-mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]. We determined the subcellular distribution of HMG-CoA reductase at high resolution by means of immunoelectron microscopy on ultrathin frozen liver sections of rats treated with lovastatin and cholestyramine. High concentrations of reductase were located on the outer (cytoplasmic) surfaces of smooth endoplasmic reticulum (SER) membranes induced in hepatocytes by acute drug administration. The enzyme was specifically localized over the whorled SER membranes and was absent from nonwhorled SER, rough endoplasmic reticulum, and peroxisomes. Intense HMG-CoA reductase labeling was only observed in hepatocytes containing high levels of HMG-CoA reductase activity; no staining was detected in untreated livers. These observations show that HMG-CoA reductase is induced as an integral component of the SER membranes that form in rat hepatocytes subsequent to lovastatin treatment and suggest that the formation of SER whorls in rat hepatocytes is due to mechanism-based effects of lovastatin.
Singer
I I
II
Department of Biochemical and Molecular Pathology, Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
Scott
S
S
Kazazis
D M
DM
Huff
J W
JW
D000818:Animals; D002792:Cholestyramine Resin / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008854:Microscopy, Electron; D051381:Rats; D011919:Rats, Inbred Strains
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002792:Cholestyramine Resin; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent