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Inhibition of cholesterol synthesis and hepatic 3-hydroxy-3-methylglutaryl--CoA reductase in rats by simvastatin and pravastatin. 1995

M Del Puppo, and S Rauli, and M Galli Kienle
Department of Medical Chemistry and Biochemistry, University of Milan, Italy.

In this communication we attempt to provide one possible explanation for the observed differences regarding kinetics and distribution between simvastatin and pravastatin. Rats treated with simvastatin or pravastatin exhibited a reduction in the incorporation of [2-(14)C] acetate into liver cholesterol and displayed lower plasma mevalonate levels as compared to control animals. Moreover, both the total and dephosphorylated 3-hydroxy-3-methylglutaryl--CoA (HMG-CoA) reductase (EC 1.1.1.34) activities, particularly 1 h after treatment, were greatly reduced in liver microsomes obtained from simvastatin-treated as compared to control rats. During the same time frame, these parameters were actually elevated with pravastatin treatment. It is known that HMG-CoA reductase synthesis and activity increase following their competitive inhibition. Our results suggest that pravastatin, at 1 h following treatment, was no longer bound to the enzyme; however, it had entered the liver because its inhibitory effect on cholesterol synthesis was manifest at early times after administration. These data provide a plausible rationale for the earlier observation that activity of simvastatin persists longer in plasma than does that of pravastatin.

UI MeSH Term Description Entries
D008148 Lovastatin A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Lovastatin, 1 alpha-Isomer,Mevinolin,6-Methylcompactin,Lovastatin, (1 alpha(S*))-Isomer,MK-803,Mevacor,Monacolin K,1 alpha-Isomer Lovastatin,6 Methylcompactin,Lovastatin, 1 alpha Isomer,MK 803,MK803,alpha-Isomer Lovastatin, 1
D008297 Male Males
D008798 Mevalonic Acid A dihydroxy monocarboxylic acid and precursor in the biosynthetic pathway known as the mevalonate pathway, which produces terpenes and steroids that are vital for diverse cellular functions. Mevalonate,Acid, Mevalonic
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D002784 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Epicholesterol
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000924 Anticholesteremic Agents Substances used to lower plasma CHOLESTEROL levels. Cholesterol Inhibitors,Hypocholesteremic Agents,Anticholesteremic Drugs,Anticholesteremics,Inhibitors, Cholesterol,Agents, Anticholesteremic,Agents, Hypocholesteremic,Drugs, Anticholesteremic
D017035 Pravastatin An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES). Eptastatin,Apo-Pravastatin,Bristacol,CS-514,Elisor,Lin-Pravastatin,Lipemol,Liplat,Lipostat,Mevalotin,Nu-Pravastatin,Prareduct,Pravachol,Pravacol,Pravasin,Pravastatin Monosodium Salt, (6 beta)-Isomer,Pravastatin Sodium,Pravastatin Sodium Salt,Pravastatin tert-Octylamine Salt,Pravastatin, (6 beta)-Isomer,RMS-431,SQ-31,000,SQ-31000,Selektine,Vasten,Apo Pravastatin,CS 514,CS514,Lin Pravastatin,Nu Pravastatin,Pravastatin tert Octylamine Salt,RMS 431,RMS431,SQ 31,000,SQ 31000,SQ31,000,SQ31000,Sodium Salt, Pravastatin
D017207 Rats, Sprague-Dawley A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company. Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats

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