Drugs online research references
Atherosclerosis. 1996 Oct 25;126(2):221-6.
Effects of gemfibrozil administration on very low density lipoprotein receptor mRNA levels in rabbits.
Matsuoka N, Jingami H, Masuzaki H, Mizuno M, Nakaishi S, Suga J, Tanaka T, Yamamoto T, Nakao K.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
To elucidate the regulation of very low density lipoprotein (VLDL) receptor gene expression, we administered to rabbits for 14 days gemfibrozil, a fabric acid derivative and a lipid lowering drug that is also included among peroxisome proliferators. VLDL receptor mRNA levels were examined by Northern blot analysis. The VLDL receptor mRNA levels in retroperitoneal adipose tissue and in gastrocnemius muscle were increased 6.9-fold and 3.7-fold, respectively, with gemfibrozil treatment, but no marked changes were observed in the heart, the organ in which VLDL receptor is most highly expressed. In the liver, VLDL receptor mRNA was not detected either before or after gemfibrozil administration. Lipoprotein lipase (LPL) and long-chain acyl coenzyme A synthetase (ACS) mRNA levels were also increased in parallel in adipose tissue. The enhanced expression of VLDL receptor mRNA may contribute to the increase of triglyceride-rich lipoprotein catabolism in peripheral tissues such as adipose tissue and muscles.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8902147&dopt=Abstract
Hepatology. 1984 May-Jun;4(3):520-30.
Quantitative microscopy comparison of peroxisome proliferation by the lipid-regulating agent gemfibrozil in several species.
Gray RH, de la Iglesia FA.
Peroxisome proliferation, a well-documented subcellular reaction which follows the administration of hypolipidemic agents, has been well studied in rodents. However, quantitative studies of this phenomenon in other species of laboratory animals are not readily available even though these species are commonly used as predictors of tolerance or safety in humans. The quantitative stereologic studies reported here compared the effects of the new hypolipidemic agent gemfibrozil on hepatic peroxisomes of monkeys, dogs, hamsters and rats of both sexes under several treatment schedules. Gemfibrozil was administered to rats at 300 mg per kg per day for 1 year in the diet; to hamsters at 400 mg per kg per day for 2 weeks by diet admixture; to dogs at 300 mg per kg per day in gelatin capsules for 1 year; and to monkeys at 300 mg per kg day for 3 months by gavage. These dose levels were selected on the basis of tolerance from preliminary studies in each species. At the end of each experimental interval, liver samples were processed for quantitative microscopy. Peroxisomes from male rats were enlarged and the number of peroxisomes per cell were increased 7-fold over controls, resulting in a 20-fold increased peroxisome volume per cell. Statistically, significant increases also occurred in female rats and the difference between treated and controls was 3-fold for both number and volume of peroxisomes per cytoplasmic unit volume. In hamsters, peroxisomes were proliferated and were of significantly smaller size to the extent that the volume of cytoplasm occupied by peroxisomes was not significantly changed. In dogs, the number of peroxisomes per cell was increased and the volume fraction was significantly increased in females only. The number of peroxisomes in young monkeys did not change after treatment, and the peroxisome volume was decreased in males and increased in females. Aged monkeys had increased number of peroxisomes per hepatocyte with increased volume fraction. These results indicate significant differences in the magnitude and direction of peroxisome changes, reflecting species-dependent organelle response to hypolipidemic agents. The order of susceptibility of peroxisome proliferation in laboratory animals is dog less than monkey less than hamster less than rat.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6586630&dopt=Abstract
J Lipid Res. 1995 Dec;36(12):2541-51.
Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action.
Haubenwallner S, Essenburg AD, Barnett BC, Pape ME, DeMattos RB, Krause BR, Minton LL, Auerbach BJ, Newton RS, Leff T, et al.
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48106, USA.
For the last 30 years fibrates have been widely prescribed to treat human dyslipidemia. However, the primary mechanism by which they lower plasma lipid levels is still unknown. Studies with transgenic mice have suggested that changes in apoC-III expression levels have a dramatic influence on plasma triglyceride levels. These results suggested that fibrates could reduce lipid levels by lowering apoC-III gene expression. In the current studies, we sought to determine whether the selected fibrates, bezafibrate, clofibrate, fenofibrate, and gemfibrozil, could reduce hepatic apoC-III mRNA and plasma apoC-III levels. Chow-fed rats were orally gavaged daily with a dosing vehicle alone or with 100 mg/kg of each of the fibrates for 1 week and in addition with gemfibrozil for 2 weeks. Bezafibrate and fenofibrate lowered plasma triglyceride by approximately half and dramatically reduced hepatic apoC-III mRNA and plasma apoC-III levels. In contrast, clofibrate did not reduce plasma triglyceride levels and only partially reduced apoC-III mRNA and plasma protein levels. Gemfibrozil strongly reduced plasma triglyceride levels and had an intermediate but significant effect on apoC-III mRNA and plasma apoC-III levels. Some of the fibrates, especially gemfibrozil also reduced plasma apoC-II levels, an effect that could contribute to the observed triglyceride-lowering effect. In addition, the ratio of plasma apoE to plasma apoC-II plus apoC-III was strongly and inversely correlated with plasma triglyceride levels. As plasma apoE levels were not reduced in gemfibrozil-treated animals, this could also have contributed to the triglyceride-lowering effect of this fibrate. Fibrate-mediated triglyceride lowering was not the result of a decreased apoB or VLDL production and, therefore, suggested an enhanced VLDL remnant catabolism. Our results suggest that the mechanism by which fibrates lower plasma triglycerides is by reducing the level of hepatic apoC-III expression.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8847480&dopt=Abstract
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