High doses of atorvastatin and simvastatin induce key enzymes involved in VLDL production.

Treatments with high doses of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors may induce the expression of sterol regulatory element binding protein (SREBP)-target genes, causing different effects from those attributed to the reduction of hepatic cholesterol content. The aim of this study was to investigate the effects of high doses of statins on the key enzymes involved in VLDL production in normolipidemic rats. To examine whether the effects caused by statin treatment are a consequence of HMG-CoA reductase inhibition, we tested the effect of atorvastatin on these enzymes in mevalonate-fed rats.

Increase in hepatic expression of SREBP-2 by gemfibrozil administration to rats.

It is well known that gemfibrozil increases the biliary output of cholesterol and phospholipids, but we have little knowledge about the impact these changes have on liver cholesterol and phospholipid biosynthetic pathways. In the present study, no changes were detected in liver lipids and CTP:phosphocholine cytidylyltransferase after gemfibrozil administration to rats. On the contrary, 3-hydroxy-3-methylglutaryl-CoA reductase mRNA (9.

Bezafibrate induces acyl-CoA oxidase mRNA levels and fatty acid peroxisomal beta-oxidation in rat white adipose tissue.

Rats treated with bezafibrate, a PPAR activator, gain less body weight and increase daily food intake. Previously, we have related these changes to a shift of thermogenesis from brown adipose tissue to white adipose tissue attributable to bezafibrate, which induces uncoupling proteins (UCP), UCP-1 and UCP-3, in rat white adipocytes. Nevertheless, UCP induction was weak, implying additional mechanisms in the change of energy homeostasis produced by bezafibrate.

Peroxisome proliferator-activated receptor alpha (PPARalpha) activators, bezafibrate and Wy-14,643, increase uncoupling protein-3 mRNA levels without modifying the mitochondrial membrane potential in primary culture of rat preadipocytes.

Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters which act as pores for H(+) ions, dissipating the electrochemical gradient that develops during mitochondrial respiration at the expense of ATP synthesis. We have studied the effects of two fibrates, bezafibrate and Wy-14,643, on UCP-3 and UCP-2 mRNA levels in primary monolayer cultures of rat adipocytes and undifferentiated preadipocytes. Treatment with both PPARalpha activators for 24 h up-regulated UCP-3 mRNA levels.

Etomoxir, sodium 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, up-regulates uncoupling protein-3 mRNA levels in primary culture of rat preadipocytes.

Uncoupling proteins (UCPs) are mitochondrial membrane proton transporters that uncouple respiration from oxidative phosphorylation by dissipating the proton gradient across the membrane. Treatment of primary culture of rat preadipocytes for 24 h with 40 microM etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase I (CPT-I), up-regulated UCP-3 mRNA levels (3. 6-fold induction), whereas changes in UCP-2 mRNA levels were not significant.

Different effect of simvastatin and atorvastatin on key enzymes involved in VLDL synthesis and catabolism in high fat/cholesterol fed rabbits.

The effects of atorvastatin (3 mg kg(-1)) and simvastatin (3 mg kg(-1)) on hepatic enzyme activities involved in very low density lipoprotein metabolism were studied in coconut oil/cholesterol fed rabbits. Plasma cholesterol and triglyceride levels increased 19 and 4 fold, respectively, after 7 weeks of feeding. Treatment with statins during the last 4 weeks of feeding abolished the progression of hypercholesterolaemia and reduced plasma triglyceride levels.

Uncoupling protein-3 mRNA levels are increased in white adipose tissue and skeletal muscle of bezafibrate-treated rats.

Fibrates are hypolipidemic drugs that are also able to improve glucose tolerance in animals and diabetic patients through an unknown mechanism. Since uncoupling proteins (UCP) seem to play an important role in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether treatment of rats with bezafibrate for 3, 7, or 15 days modified UCP mRNA levels. Using RT-PCR, we observed a weak ectopic expression of UCP-1 and a 2-fold increase in UCP-3 mRNA levels in white adipose tissue after 7 and 15 days of treatment.

Effect of hypolipidemic drugs on key enzyme activities related to lipid metabolism in normolipidemic rabbits.

The effect of atorvastatin (3 mg kg(-1) day(-1)), simvastatin (3 mg kg(-1) day(-1)) and bezafibrate (100 mg kg(-1) day(-1)) administered for 4 weeks to male New Zealand white rabbits on enzyme activities related to lipid metabolism has been studied. Only the statins reduced plasma cholesterol values, while none of the drugs modified plasma triglyceride or high density lipoprotein (HDL)-cholesterol concentrations, nor the activity of enzymes such as hepatic diacylglycerol acyltransferase, lipoprotein lipase or hepatic lipase, directly involved in triglyceride metabolism. Both statins elicited similar increases in the hepatic microsomal 3-hydroxy-3-methyl-glutaryl Coenzyme A (CoA) reductase activity (147 and 109% induction for simvastatin and atorvastatin, respectively), and none of the drugs assayed modified hepatic acyl-coenzyme A:cholesterol acyltransferase activity significantly.

Influence of lipid profile and fatty acid composition on the oxidation behavior of rat and guinea pig low density lipoprotein.

Low density lipoprotein (LDL) oxidation is one of the first steps proposed for the development of atherosclerosis. Since lipid profile and fatty acid composition may affect this process, we studied the influence of these factors on the oxidation behavior of rat and guinea pig LDL. Marked compositional differences were observed.

Different effects of fibrates on the microsomal fatty acid chain elongation and the acyl composition of phospholipids in guinea-pigs.

1. The effects in vitro and in vivo of three fibric acid derivatives, clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on some enzyme activities related to fatty acid biosynthesis, namely palmitoyl-CoA synthetase and hydrolases (microsomal and cytosolic), NADH and NADPH cytochrome c reductases and acyl-CoA elongases were investigated in guinea-pigs. 2.

Differential effects of fibrates on the acyl composition of microsomal phospholipids in rats.

1. The time-course and comparative effects of treatment with clofibrate (CFB), bezafibrate (BFB), and gemfibrozil (GFB) on the acyl composition of the main microsomal phospholipids, i.e.

Selective modification of rat hepatic microsomal fatty acid chain elongation and desaturation by fibrates: relationship with peroxisome proliferation.

1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-, palmitoleoyl- and gamma-linolenoyl-CoA elongase, delta-9, delta-6 and delta-5 desaturase activities, and microsomal electron transport chains, as well as the correlation with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2.

Relationship between plasma lipids and palmitoyl-CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates.

1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-CoA hydrolase and synthetase activities, as well as the correlations with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2.

Fibrates modify rat hepatic fatty acid chain elongation and desaturation in vitro.

Three fibric acid derivatives, clofibric acid (CFB), bezafibrate (BFB), and gemfibrozil (GFB), mainly used in the treatment of hypertriglyceridaemic or mixed hyperlipidaemic states, have been tested for their ability to modify fatty acid chain elongation and desaturation in vitro. Both endogenous and exogenous (saturated, monounsaturated and polyunsaturated) fatty acid elongations were inhibited by fibrates at concentrations well within the physiological range (IC50 values for GFB were between 0.1 and 0.

Pharmacokinetics and oral bioavailability of carbimide in man.

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0.

Uranium accumulation by Pseudomonas sp. EPS-5028.

Pseudomonas sp. EPS-5028 was examined for the ability to accumulate uranium from solutions. The uptake of uranium by this microorganism is very rapid and is affected by pH but not by temperature, metabolic inhibitors, culture time and the presence of various cations and anions.

Spectrophotometric determination of the stability of an ampicillin-dicloxacillin suspension.

The degradation rate constants for ampicillin and for dicloxacillin in the suspension filtrate, and their solubility coefficients (at 25 degrees C) were determined by spectrophotometry employing a multicomponent computer program. The shelf life of the ampicillin-dicloxacillin suspension was then determined in terms of the stability of ampicillin, the least stable component.

In vitro study of caffeic acid-bovine serum albumin interaction.

Caffeic acid, a natural product with pharmacological properties, such as DOPA-decarboxylase and 5-lipooxygenase inhibition, has been tested in vitro for its binding ratio to bovine serum albumin. This study was carried out by means of four analytical methods. Equilibrium dialysis has been proved to be the most reliable in determination of total binding sites, while acid precipitation has been evaluated as a model of irreversible binding.

Hepatoprotective activity of polyphenolic compounds from Cynara scolymus against CCl4 toxicity in isolated rat hepatocytes.

The hepatoprotective activity against CCl4 toxicity in isolated rat hepatocytes of some polyphenolic compounds, such as cynarin, isochlorogenic acid, chlorogenic acid, luteolin-7-glucoside, and two organic acids, caffeic and quinic, from Cynara scolymus, is tested. Only cynarine and, to a lesser extent, caffeic acid showed cytoprotective action. The possible relationship between the molecular structure and the protective effect found is discussed.