Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase induce reductase accumulation and altered lamellar bodies in rat forestomach keratinocytes.
Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and a potent hypocholesterolemic agent, induces a hyperplastic thickening of the rat forestomach mucosa after oral administration of its active form, a hydroxyacid. We studied the effects of lovastatin on the intracellular accumulation of HMG-CoA reductase immunostaining and the accompanying morphological changes in rat forestomach keratinocytes by immunofluorescence microscopy and transmission electron microscopy (TEM). Administration of lovastatin hydroxyacid induced increases in HMG-CoA reductase levels within forestomach keratinocytes that were dose and time dependent and reversible. The adjacent glandular stomach epithelium did not exhibit induction of reductase. A pharmacologically inactive epimer of lovastatin hydroxyacid did not increase keratinocyte reductase accumulation, and lovastatin lactone induced minimal forestomach reductase. TEM of forestomachs from rats given lovastatin hydroxyacid demonstrated profound alterations in epidermal lamellar bodies (organelles that transport lipids and steroids to the intercellular spaces of the stratum corneum). Treated cells lacked internal lipid lamellae and failed to secrete sheets of lipid material into the intercellular spaces of the stratum corneum. We hypothesize that sustained inhibition of HMG-CoA reductase in rat forestomach keratinocytes induces accumulation of HMG-CoA reductase and hyperplasia by inhibiting sterol synthesis, assembly of lamellar bodies, and formation of intercellular lipid sheets.
Singer
I I
II
Department of Biochemical and Molecular Pathology, Merck Sharp & Dohme Research Laboratories, Merck & Co., Inc., Rahway, N.J. 07065.
Kawka
D W
DW
Scott
S
S
Bailey
P
P
Kloss
M W
MW
Majka
J
J
MacDonald
J S
JS
D000818:Animals; D005260:Female; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006965:Hyperplasia / Q000209:etiology; D015603:Keratinocytes / Q000201:enzymology / Q000648:ultrastructure*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology*; D008854:Microscopy, Electron; D015388:Organelles / Q000648:ultrastructure*; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C040295:mevinolinic acid; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases