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Cholestrol content of the rat lens is lowered by administration of simvastatin, but not pravastatin

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Author: Vries, A.C.J. de · Vermeer, M.A. · Bredman, J.J. · Bar, P.R. · Cohen, L.H.
Type:article
Date:1993
Institution: Instituut voor verouderings- en vaatziekten onderzoek TNO
Source:Experimental Eye Research, 4, 56, 393-399
Identifier: 232101
doi: doi:/10.1006/exer.1993.1053
Keywords: Pharmacology · 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors · hypocholesterolaemic drugs · antilipemic agent · drug derivative · hydroxymethylglutaryl coenzyme A reductase inhibitor · hypocholesterolemic agent · mevinolin · animal experiment · cholesterol metabolism · oral drug administration · biosynthesis · dose response · drug effect · enzymology · liver microsome · metabolism · organ culture · rat strain · time · Aging · Animal · Anticholesteremic Agents · Antilipemic Agents · Cholesterol · Dose-Response Relationship, Drug · Hydroxymethylglutaryl-CoA Reductase Inhibitors · Lens, Crystalline · Lovastatin · Microsomes, Liver · Organ Culture · Pravastatin · Rats · Rats, Wistar · Simvastatin · Time Factors

Abstract

The influence of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors pravastatin and simvastatin on lens cholesterol metabolism was investigated in the rat. Short-term organ culture experiments with explanted lenses from 21-day-old Wistar rats showed that simvastatin was at least 35 times more effective than pravastatin in inhibiting cholesterol synthesis. In vivo the cholesterol content of the rat lens increased linearly with age. Experiments were designed to answer the question whether simvastatin and pravastatin inhibit lens cholesterol synthesis in vivo, which would result in a reduced cholesterol accumulation in the lens with age. Young Wistar rats were weaned at an age of 21 days and had ad libitum access to a chow supplemented with 10-100 mg vastatin kg-1 (drug consumption: 1.5-15 mg vastatin kg-1 body weight day-1, respectively) or no additions for 3 weeks. Both drugs induced the HMG-CoA reductase activity in rat liver microsomes (isolated after 1, 2 and 3 weeks of treatment) to a similar extent. This indicates that the two drugs inhibited hepatic cholesterol synthesis to a comparable extent. During the whole treatment period no significant differences between control and drug-treated animals could be observed when the wet weight and protein content of the lenses were considered. However, a striking difference between the control group and pravastatin group (50 mg drug kg-1 diet) on the one hand and the simvastatin group (50 mg drug kg-1 diet) on the other was observed when the cholesterol content of the lenses were compared as a function of age. After 1 week of treatment all three groups showed the same increase in cholesterol content. Thereafter, the simvastatin group showed little additional increase, whereas the pravastatin group and the control group showed the same increase in cholesterol content (from 20 to 40 μg per lens). Even at a concentration of 100 mg kg-1 chow, pravastatin had no effect after 3 weeks, whereas at this concentration simvastatin already caused a reduction in lens cholesterol content after 7 days of treatment. Simvastatin in a concentration of 10 mg kg-1 chow reduced lens cholesterol by more than 2 5% after 3 weeks. So, we observed at least a ten-fold difference between both drugs in the ability to affect the cholesterol content of the lens in vivo. Furthermore, our observations indicate that in the avascular lens the accumulation of cholesterol with age is largely dependent on in situ de novo synthesis, and that under these in vivo conditions simvastatin, but not pravastatin, inhibits cholesterol synthesis in the lens. Chemicals/CAS: cholesterol, 57-88-5; pravastatin, 81131-74-0; simvastatin, 79902-63-9; Anticholesteremic Agents; Antilipemic Agents; Cholesterol, 57-88-5; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin, 75330-75-5; Pravastatin, 81093-37-0; Simvastatin, 79902-63-9