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PubMed2004

Marine Neurotoxins: Envenomations and Contact Toxins.

Familiarity with the appearance and habitat of venomous sea creatures, the location of their stinging apparatus, and surveillance of population concentrations within recreational waters are essential in avoiding envenomations. Compared with the thermo-stable low molecular weighted ingestible seafood toxins, venomous toxins are often large molecular weight proteins and many are heat labile, which provides opportunity for therapeutic intervention. Heat therapy may denature the toxins, and provide immediate relief of pain in coelenterate and venomous fish envenomations. Injections of local anesthetic agents may also be used. First aid measures at the seashore may limit the spread of venom, and include immobilization of the affected sites, compression bandaging, and venous-lymphatic occlusive bandages. Measures to limit continued envenomation by attached stinging cells include topical vinegar for jellyfish tentacles and irrigation with debridment for spines of venomous fish. Antivenins are of limited availability and may be used for envenomations with sea snakes, Chironex box jellyfish, and some venomous fish. Sea snakes bites may be treated with antivenin from land snakes or with hemodialysis when antivenin is not available. Neuromuscular paralysis occurs with bites by sea snakes, cone snails, blue octopuses, and some jellyfish. Supportive treatment includes attention to cardiopulmonary resuscitation and intubation. Exposure to Pfeisteria may result in cognitive and behavioral abnormalities. Treatment with cholestyramine may be helpful in binding the toxin and improve recovery.

Journal Article↗

PubMed1985

Nonpharmacologic and pharmacologic alteration of high-density lipoprotein cholesterol: therapeutic approaches to prevention of atherosclerosis.

High-density lipoprotein (HDL) cholesterol, an independent coronary heart disease (CHD) risk factor, is inversely associated with CHD. Whether interventions to increase concentrations of HDL--particularly the HDL2, HDL3, and apolipoprotein A1 subfractions--will reduce the incidence of CHD in high-risk patients is thus an area of intense speculation. Both nonpharmacologic and pharmacologic regimens will raise HDL concentrations. Nonpharmacologic approaches include habitual high-level aerobic exercise and weight loss--both of these somewhat more effective in men than in women--cessation of cigarette smoking, and changing of dietary habits. A number of drugs have been found to elevate HDL cholesterol. These include the bile acid-binding resin cholestyramine, nicotinic acid, gemfibrozil, phenytoin, exogenous estrogens, and alcohol. Terbutaline has also been reported to raise HDL cholesterol. It is not yet known whether, and to what degree, pharmacologic and nonpharmacologic elevation of HDL cholesterol will retard or reverse the progression of atherosclerosis. Conversely, HDL cholesterol is lowered by a broad variety of drugs, including anabolic--androgenic steroids, exogenous progestins, and probucol, which are used therapeutically to reduce low-density lipoprotein (LDL) cholesterol. Some agents used to treat hypertension also reduce HDL cholesterol, especially thiazide diuretics and the beta blockers, with the possible exception of pindolol. In the antiadrenergic class of antihypertensive agents, reserpine and methyldopa lower HDL cholesterol, but the alpha blocker prazosin does not appear to affect HDL cholesterol. The alpha agonist guanabenz has no effect on HDL cholesterol, and the vasodilator carprazidil has been reported to raise HDL cholesterol. In light of these facts, investigations should be undertaken to determine whether the metabolic effects of antihypertensive agents blunt their beneficial effects on CHD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1985

Primary prevention of coronary heart disease by lowering lipids: results and implications.

Evidence to support the hypothesis that lowering total and low-density lipoprotein (LDL) cholesterol may reduce heart attacks and heart deaths has, until recently, not been available. Early primary prevention trials lacked definitive data on these "hard" end points. Since 1980, five primary prevention trials have attempted to demonstrate the benefit of lowering cholesterol. Three of these involved diet: the Oslo Heart Trial and both the European and American Multiple Risk Factor Intervention Trials (MRFITs). Two involved lipid-lowering drugs: the European Clofibrate Primary Prevention Trial and the National Heart, Lung, and Blood Institute's recently concluded Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). The Olso Heart Trial suggested a benefit from the dietary reduction of cholesterol; results of the other studies of diet were equivocal. Although clofibrate did demonstrate a reduced incidence of heart attacks in the treated group, the cardiac mortality rate was not altered in this group. A significant increase in the all-cause mortality rate (other than ischemic heart disease) observed in this trial in treated subjects makes clofibrate difficult to recommend. The LRC-CPPT study, involving cholestyramine, has provided conclusive evidence concerning the benefits of lowering cholesterol: significant reductions were observed in all cardiovascular end points measured, including the development of angina and positive exercise stress tests, referral for bypass surgery, and the hard primary study end point heart attack and heart attack death.

Cholesterol, LDL↗

PubMed1988

Review of major intervention studies in hypertension and hyperlipidemia: focus on coronary heart disease.

The ultimate aim in treating hypertension and hyperlipidemia is to reduce cardiovascular mortality and morbidity, especially strokes and coronary events, for example, fatal and nonfatal myocardial infarction and sudden death. Extensive intervention studies in moderate-to-severe hypertension have revealed the significance of antihypertensive therapy in reducing total cardiovascular mortality and morbidity, particularly from cerebrovascular causes. However, the reduction of coronary events has not been equally successful. The situation in mild-to-moderate hypertension is even more disappointing: recent studies, such as the Medical Research Council hypertension trial, the international Prospective Primary Prevention Study in Hypertension, and the Heart Attack Primary Prevention in Hypertensives trial could not demonstrate any benefit from antihypertensive treatment with beta-blockers or diuretics in the prevention of coronary heart disease. The reasons for these negative results are not obvious. However, metabolic side effects associated with certain antihypertensive drugs, which counteract the beneficial effects of blood pressure reduction, are one topic of discussion. For the genesis of atherosclerosis of the coronary vasculature, hyperlipoproteinemia appears to be of greater importance than hypertension and has to be treated simultaneously. Two extensive intervention studies, the Lipid Research Clinics coronary primary prevention trial and the Helsinki Heart Study, showed a significant reduction of coronary events with lipid-lowering treatments with cholestyramine and gemfibrozil, respectively. These findings are in agreement with the results of a recent secondary prevention study, which showed a regression of atherosclerosis in coronary arteries and aortocoronary bypass grafts. Moreover, antihypertensive treatment aimed at a reduction in coronary heart disease has to focus on serum lipids, especially in mild hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Prevention or reversal of atherosclerosis: review of current evidence.

Treatment with lipid-reducing agents is associated with reduced morbidity and mortality from coronary heart disease. Such treatment appears to work at the level of the atherosclerotic lesion, causing stabilization, slowed progression and, in some cases, regression of lesions. Morbidity and mortality studies of cholestyramine and gemfibrozil treatment have shown that a reduction of lipid levels was associated with reduced mortality from coronary heart disease; niacin treatment has been shown to have long-term effects on reducing cardiovascular mortality. Angiographic studies have documented that beneficial effects of treatment with lipid-reducing agents and intensive computer-assisted diet counseling occur at the level of the coronary atherosclerotic lesion.

Angiography↗

PubMed1990

Lovastatin and simvastatin prevention studies.

There is substantial evidence that drug treatment of hypercholesterolemia in patients without known coronary artery disease (CAD) can reduce fatal and nonfatal CAD events. Two trials, the Lipid Research Clinics Coronary Primary Prevention Trial and the Helsinki Heart Study used cholestyramine and gemfibrozil, respectively, to alter lipoprotein levels; their demonstrated efficacy and safety have led to their widespread use in hyperlipidemic patients. Recently, a new class of hypolipidemic agents has been shown to be extremely effective in lowering total and low-density lipoprotein cholesterol levels. These drugs, including lovastatin and simvastatin, competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of intracellular cholesterol synthesis. Results of safety and efficacy studies suggest that they may be valuable first-line treatment options for high-risk hypercholesterolemic patients. Two long-term clinical trials are planned with lovastatin and simvastatin. In the United States, lovastatin will be used in a double-blind, placebo-controlled, primary prevention trial involving 8,000 patients without clinical evidence of CAD, slight to moderate elevations of total cholesterol, and low- and high-density lipoprotein cholesterol to establish whether 5 years of treatment will decrease the rate of fatal CAD or nonfatal myocardial infarction. A Scandinavian study of 4,000 patients with ischemic heart disease and hypercholesterolemia will determine if simvastatin will improve total survival and reduce fatal or nonfatal myocardial infarction and sudden death for at least 3 years. These study designs will be discussed and compared with other studies, and the expected impact on CAD event rates presented.

Anticholesteremic Agents↗

PubMed1990

Clinical trials including an update on the Helsinki Heart Study.

The incidence of myocardial infarction (MI), sudden death and other clinical manifestations of coronary heart disease can be reduced by lowering the blood cholesterol level. This is now well established by multiple clinical trials using a variety of interventions including diet and lipid-lowering drugs. Dietary studies in Los Angeles and in Oslo, Norway, have induced a reduction in blood cholesterol of between 10 and 15% with correlated reductions in coronary disease of 20 to 50%. Both niacin and clofibrate in separate cohorts demonstrated a significant reduction in new MI during 5 years of treatment in the Coronary Drug Project. Similar reductions in new MI occurred in the World Health Organization Study with clofibrate. However, in this trial and different from all other trials, mortality in the drug-treatment group actually increased. This finding remains unexplained. In the more recent Lipid Research Clinics Coronary Primary Prevention Trial using the bile acid-binding resin cholestyramine, only a 9% reduction in total cholesterol resulted in a highly significant reduction in the major end points--MI and sudden death--as well as in other secondary end points, including the need for coronary artery bypass graft surgery, ischemic changes on exercise electrocardiography and new-onset angina. Recently, another primary prevention trial using gemfibrozil produced a similar reduction in total cholesterol but a much more significant increase in high-density lipoprotein cholesterol. The reduction in coronary heart disease was in excess of 34% and was strongly related to both low-density lipoprotein cholesterol reduction and high-density lipoprotein elevation. Combination drug studies have produced larger reductions in total cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

How effective is drug therapy in heterozygous familial hypercholesterolemia?

The goals of drug therapy in adult patients with heterozygous familial hypercholesterolemia (FH) are directed at reducing plasma concentrations of low density lipoproteins (LDL), with a secondary goal in selected patients to concurrently decrease elevated plasma concentrations of lipoprotein(a), triglycerides, and potentially exert favorable effects on the concentrations of high density lipoproteins (HDL). Desirable goals of therapy are to reduce concentrations of LDL cholesterol to < 130-160 mg/dL in patients without evidence of coronary artery disease, and, in my opinion, to < 100 mg/dL in patients with evidence of coronary artery disease. The bile acid sequestrants, cholestyramine and colestipol, reduce LDL concentrations by 23-36%, when given in doses of 4-6 scoops/day, but reduce LDL concentrations to desirable levels in only 10-15% of patients. Similarly, nicotinic acid, in doses of 3-6 g/day, is capable of reducing LDL concentrations by up to 30%, but the majority of patients still remain hypercholesterolemic. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which include lovastatin, simvastatin, and pravastatin, are the most effective of the currently available drugs and show dose-dependent effects on the concentrations of LDL cholesterol, which decrease by 20-45% in response to these drugs when used over the full dosage range. However, even with these agents, concentrations of LDL cholesterol remain > 200 mg/dL in one-third of male and female patients with heterozygous FH and remain > 160 mg/dL in 75-80% of treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticholesteremic Agents↗

PubMed1994

Clinical implications of the biopharmaceutical properties of fluvastatin.

Fluvastatin sodium (Lescol; Sandoz) the first entirely synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor studied, is structurally distinct from the other HMG-CoA reductase inhibitors currently available, all of which are fungal metabolites and analogues of compactin. Fluvastatin's distinct structure may be responsible for the biopharmaceutical properties that result in its low systemic exposure and, subsequently, low incidence of peripheral adverse events, such as headache and myositis. Fluvastatin is rapidly absorbed from the gastrointestinal tract; has a 30-minute half-life, the shortest of any currently available HMG-CoA reductase inhibitor (lovastatin, 15 hours; pravastatin, 2 hours; simvastatin, 15.6 hours); is highly selective for the liver, undergoing extensive first-pass metabolism; has no active circulating metabolites; and does not penetrate the blood-brain barrier, unlike lovastatin and simvastatin. The low systemic exposure suggests that the occurrence of peripheral adverse events, such as myositis, central nervous system effects, and drug-drug interactions, may be less than what is currently observed with other HMG-CoA reductase inhibitors. Neither niacin nor propranolol had an effect on fluvastatin plasma levels when combined with fluvastatin. In contrast to other HMG-CoA reductase inhibitors, fluvastatin in combination with niacin resulted in no instances of myositis or other serious adverse events. Although the interaction of fluvastatin with cholestyramine resulted in a lower rate and extent of fluvastatin bioavailability, this reduction had no impact on clinical efficacy. Fluvastatin administered to patients chronically receiving digoxin had no effect on the area under the curve (AUC) of digoxin compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1978

Continuous flow plasma exchange in the treatment of homozygous familial hypercholesterolemia.

We report the clinical and laboratory effects of continuous-flow plasma exchange in two patients suffering from homozygous familial hypercholesterolemia. In one (Case 1) plasmapheresis was performed at fortnightly intervals over a period of 18 months; in the other (Case 2) the necessity for surgical relief of an associated supravalvular aortic stenosis resulted in premature termination of the trial. The plasma cholesterol levels in both patients fell by 35 per cent from the mean before study in the course of treatment. In Case 1 this was associated with marked regression of the patient's xanthomas, disappearance of the S-T segment depression seen on effort electrocardiograms obtained prior to the introduction of plasmapheresis, possible widening of the stenosis present at the origin of the left anterior descending coronary artery, and a marked increase in exercise tolerance and diminished frequency of anginal attacks. Cessation of cholestyramine and clofibrate administration during this study did not in any way reverse the reduction of plasma cholesterol achieved by means of plasmapheresis combined with drug therapy. We conclude that plasmapheresis has a role to play in the management of patients with homozygous familial hypercholesterolemia.

Adolescent↗

PubMed1994

Fluvastatin Long-Term Extension Trial (FLUENT): summary of efficacy and safety.

The Fluvastatin Long-Term Extension Trial (FLUENT) evaluated the safety and efficacy of fluvastatin over a period of 48 weeks. All 918 enrolled patients had severe primary hypercholesterolemia (mean baseline low-density lipoprotein [LDL] cholesterol, 227 mg/dL) and had completed one of three previous short-term studies of fluvastatin. This open-label extension study used a starting dose of 20 mg of fluvastatin at bedtime. The dose was titrated to 40 mg to achieve LDL levels of < 3.36 mmol/L (130 mg/dL). If necessary, cholestyramine was added to the fluvastatin treatment to achieve this level. After 48 weeks of treatment, the mean percent change from baseline was statistically significant for LDL (-30.7%; p < 0.001), total (-21.9%; p < 0.001), and HDL (+3.5%; p < 0.001) cholesterol. Of the 836 patients who completed the study, only four (0.5%) withdrew because of drug-related adverse events, which were mainly gastrointestinal. There was one purported case of myopathy in a patient who had a recent history of strenuous physical activity. Newly occurring or worsening lens abnormalities were generally mild and did not require discontinuation of treatment. In conclusion, these results indicate that fluvastatin is safe, effective, and well tolerated in the long-term treatment of primary hypercholesterolemia.

Adult↗

PubMed1989

Inhibition of carnitine acetyltransferase by bile acids: implications for carnitine analysis.

Carnitine acetyltransferase is used in a radioenzymatic assay to measure the concentration of carnitine. While determining the concentration of carnitine in rat bile, we found that the apparent concentration increased as bile was diluted (6.7 +/- 1.0 and 66.6 +/- 9.4 nmol/ml in undiluted and 20-fold diluted bile, respectively). The present study was designed to investigate whether a component of bile inhibited carnitine acetyltransferase. Inhibition was evaluated by measuring carnitine concentration in bile or by determining the recovery of a known amount of carnitine in the presence of bile. Inhibitory activity was extractable in organic solvents, stable to heat and base treatments, resistant to trypsin and lipase digestions, and removable by cholestyramine, a bile acid-binding resin. These results suggested that the inhibitory activity was associated with bile acids. Direct evidence was obtained by showing a reduced detectability of carnitine in the presence of individual bile acids. Chenodeoxycholic acid was the most potent inhibitor. Inhibition was unrelated to the detergent properties of bile acids. Kinetic studies revealed that carnitine acetyltransferase was inhibited competitively by chenodeoxycholic acid with a Ki of 520 microM. Bile acids also interfered in the quantitation of carnitine in cholestatic plasma. Carnitine concentration in such plasma was underestimated (17.5 +/- 2.1 mmol/ml). Reduction of bile acid concentration by a 20-fold dilution of cholestatic plasma resulted in a 3-fold higher carnitine concentration (54.6 +/- 9.0 nmol/ml). Results demonstrate that, because of the inhibition of carnitine acetyltransferase by bile acids, the radioenzymatic assay will underestimate carnitine concentration in bile or in cholestatic plasma. Accurate measurement requires either the removal of bile acids or a marked reduction in their concentration.

Acetyltransferases↗

PubMed1987

Cytochrome P-450 cholesterol 7 alpha-hydroxylase: inhibition of enzyme deactivation by structurally diverse calmodulin antagonists and phosphatase inhibitors.

Cytochrome P-450 cholesterol 7 alpha-hydroxylase (P-450Ch7 alpha) catalyzes the first and rate-limiting step in the conversion of cholesterol to bile acids. Incubation of rat liver microsomes in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer resulted in a time-dependent deactivation of P-450Ch7 alpha which was markedly accelerated by the nonionic detergent Tween 80. Microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450-dependent 7-ethoxycoumarin O-deethylase activities were unaffected under these conditions, evidencing the selectivity of the deactivation process for P-450Ch7 alpha. The rate (t 1/2 = 15-19 min at 37 degrees C) and maximal extent of P-450Ch7 alpha deactivation (greater than or equal to 90%) were both unaffected by the presence of cytosolic proteins and were also not dependent on the initial enzyme level, as shown using liver microsomes isolated from untreated, cholestyramine-fed, and xenobiotic-induced rats exhibiting an eight-fold range in P-450Ch7 alpha activity. Scavengers for reduced oxygen species were also without effect. P-450Ch7 alpha was stabilized some six- to sevenfold (t 1/2 = 94-143 min) by the phosphatase inhibitor NaF. Of a series of other phosphatase inhibitors examined, including, among others, EDTA, vanadate, and molybdate, only phosphate-containing compounds and the calmodulin antagonist trifluoperazine, and inhibitor of the Ca2+-calmodulin-dependent phosphatase calcineurin, effectively stabilized P-450Ch7 alpha. Modulation of P-450Ch7 alpha deactivation by these inhibitors generally paralleled their effects on isolated calcineurin. A variety of structurally diverse calmodulin antagonists examined were also found to effectively protect P-450Ch7 alpha from deactivation; these include calmidazolium and tamoxifen (IC50 = 25 to 50 microM), chlorpromazine, thioridazine, amitriptyline, imipramine, and the naphthalene sulfonamide compound W-7 (IC50 = 50 to 300 microM). Structure-activity analysis of several phenothiazines and their derivatives indicated that although little activity was exhibited by the sulfoxides, some protection was provided by the corresponding sulfones. On the basis of these observations, various models for the molecular basis of enzyme deactivation are considered, including the hypothesis that a calcineurin-like microsomal phosphatase mediates deactivation of this cytochrome P-450 enzyme.

Animals↗

PubMed1978

Sex-related differences in diurnal activities and development of hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase.

The activities of hepatic microsomal 3-hydroxy-3-methylglutaryl CoA reductase and cholesterol 7alpha-hydroxylase were consistently higher (up to 3-fold) in female compared to male rats fed 2% cholestyramine for 8 h daily. In all animals studied, enzymic activities were highest 6 h after feeding began. However, 85% of the rise in cholesterol 7alpha-hydroxylase activity occurred in the 6 h before and 89% of the rise in 3-hydroxy-3-methylglutaryl CoA reductase activity occurred in the 6 h after feeding started. Sex-related differences in both enzymic activities first became apparent at the time of sexual maturity. Enzymic activities before weaning were generally low and a late-suckling (13--20 days) rise in cholesterol 7alpha-hydroxylase was not accompanied by a rise in 3-hydroxy-3-methylglutaryl CoA reductase. For all of these studies we assayed cholesterol 7alpha-hydroxylase at two concentrations of exogenous cholesterol to obviate problems relating to size of the cholesterol pool.

Aging↗

PubMed1983

Hepatic microsomal activities of cholesterol 7 alpha-hydroxylase and 3-hydroxy-3-methylglutaryl-CoA reductase in the prairie dog. An animal model for cholesterol gallstone disease.

The prairie dog is a useful experimental animal model for studies of cholesterol gallstone pathogenesis. The unique susceptibility to rapid induction of gallstones solely by feeding of a 1.2% cholesterol diet in this species could result from low levels of hepatic cholesterol 7 alpha-hydroxylase. With optimal assay conditions in hepatic microsomes, a basal specific activity of about 25 pmol/min per g protein was found. Administration of diets containing 1.2% cholesterol or 5% cholestyramine caused hydroxylase levels to increase 60 and 250%, respectively. This response pattern is similar to that observed in other species under the same conditions, indicating that abnormally low basal or inappropriately unresponsive hydroxylase levels are not susceptibility factors unique to this model. With optimal assay conditions for hydroxymethylglutaryl-CoA reductase, a Km of 32.5 microM (S-HMG-CoA) and basal specific activities of between 60 and 175 pmol/min per mg protein were found. Following feeding of either sodium chenodeoxycholate or sodium cholate, in reasonable pharmacologic doses, no suppression of hydroxylase and reductase levels was found. These findings undermine the widely held view that the therapeutic effect of oral chenodeoxycholate in man for cholesterol gallstone dissolution is directly mediated by suppression of the activities of these enzymes.

Animals↗

PubMed1986

Evidence for different isotopic enrichments of acetyl-CoA used for cholesterol synthesis in the liver and intestine: a study in the rat by mass fragmentography after intravenous infusion of [13C]acetate.

Wistar rats were killed 4 h after an intravenous infusion of [1,2-13C]- and [1-14C]acetic acid sodium salt (39 mg, 12.5 microCi/ml, constant rate: 1.2 ml/h). At this time, labeled free cholesterol movements between the organs are still weak and cholesterol labeling in each tissue mainly originates from the in situ incorporation of the exogenous substrate. In male rats, the specific radioactivity of free cholesterol was found to be higher in the intestine (mucosa and wall) than in the liver and plasma. In female and in cholestyramine-fed male rats, cholesterol 14C labeling was close to that of male rats in the intestine, and was markedly higher in the liver. The same variations of 13C excess, calculated by mass fragmentography, indicated that there was no isotopic effect between 13C and 14C precursors. The advantage of this method consisted in obtaining the proportions of labeled molecules according to their molecular weight (M + 1-M + 11) for each sample. Then the distribution of 13C atoms in newly synthesized cholesterol was assessed in each sterogenesis site. In the intestine, about 3/4 of the 13C atoms were found in molecules of weight of at least M + 4 (after incorporation of at least two labeled acetate units). This proportion was only 1/3 in hepatic and plasma free cholesterol. These distinct 13C-labeling patterns clearly indicate that local variations occurred in the isotopic enrichment of acetyl-CoA used for cholesterol formation. Whatever the experimental conditions of this study, cholesterol was synthesized from an acetyl-CoA more 13C enriched in the intestine than in the liver. Such variations probably result from the different dilutions of exogenous acetyl-CoA by the endogenous pool in the liver and intestine. Consequently, the 14C or 13C incorporations measured in the liver and intestinal sterols do not account for absolute rates of cholesterol production by these organs. This study also indicated that after a few hours of infusion, free cholesterol labeling in the plasma originated mainly from cholesterol newly formed in the liver, even when acetate incorporation into cholesterol was higher in the intestine than in the liver.

Acetates↗

PubMed1987

Effects of ursodeoxycholic acid, analogues of ursodeoxycholic acid and combination of bile acids on bile acid synthesis in cultured rat hepatocytes.

The effect of individual 7 beta-hydroxy bile acids (ursodeoxycholic and ursocholic acid), bile acid analogues of ursodeoxycholic acid, combination of bile acids (taurochenodeoxycholate and taurocholate), and mixtures of bile acids, phospholipids and cholesterol in proportions found in rat bile, on bile acids synthesis was studied in cultured rat hepatocytes. Individual steroids tested included ursodeoxycholate (UDCA), ursocholate (UCA), glycoursodeoxycholate (GUDCA) and tauroursodeoxycholate (TUDCA). Analogues of UDCA (7-methylursodeoxycholate, sarcosylursodeoxycholate and ursooxazoline) and allochenodeoxycholate, a representative of 5 alpha-cholanoic bile acid were also tested in order to determine the specificity of the bile acid biofeedback. Each individual steroid was added to the culture media at concentrations ranging from 10 to 200 microM. Mixtures of taurochenodeoxycholate (TDCA) and taurocholate in concentrations ranging from 150 to 600 microM alone and in combination with phosphatidylcholine (10-125 microM) and cholesterol (3-13 microM) were also tested for their effects on bile acid synthesis. Rates of bile acid synthesis were determined as the conversion of added lipoprotein [4-14C]cholesterol or [2-14C]mevalonate into 14C-labeled bile acids and by GLC quantitation of bile acids secreted into the culture media. Individual bile acids, bile acid analogues, combination of bile acids and mixture of bile acids with phosphatidylcholine and cholesterol failed to inhibit bile acid synthesis in cultured hepatocytes. The addition of UDCA or UCA to the culture medium resulted in a marked increase in the intracellular level of both bile acids, and in the case of UDCA there was a 4-fold increase in beta-muricholate. These results demonstrate effective uptake and metabolism of these bile acids by the rat hepatocytes. UDCA, UCA, TUDCA and GUDCA also failed to inhibit cholesterol-7 alpha-hydroxylase activity in microsomes prepared from cholestyramine-fed rats. The current data confirm and extend our previous observations that, under conditions employed, neither single bile acid nor a mixture of bile acids with or without phosphatidylcholine and cholesterol inhibits bile acid synthesis in primary rat hepatocyte cultures. We postulate that mechanisms other than a direct effect of bile acids on cholesterol-7 alpha-hydroxylase might play a role in the regulation of bile acid synthesis.

Animals↗

PubMed1989

Immunochemical quantitation of fatty-acid-binding proteins. I. Tissue and intracellular distribution, postnatal development and influence of physiological conditions on rat heart and liver FABP.

Antisera against rat heart and liver fatty acid-binding protein (FABP) were applied in Western blotting analysis and ELISA to assess their tissue and intracellular distribution, and the influence of development, physiological conditions and several agents on the FABP content of tissue cytosols. The data obtained are compared with the oleic acid-binding capacity. Heart FABP is found in high concentrations in heart, skeletal muscles, diaphragm and lung, and in lower concentrations in kidney, brain and spleen, whereas liver FABP is limited to liver and intestine. In heart and liver, FABP is only present in the cytosol. The FABP content of both heart and liver shows a progressive increase during the first weeks of postnatal development, in contrast to their constant oleic acid-binding capacity. The reciprocally declining alpha-fetoprotein content of both tissues may partially account for the complementary fraction of the fatty acid-binding capacity. The FABP content and the fatty acid-binding capacity of adult heart and liver were in good accordance under various physiological conditions. Addition of clofibrate to the diet induces an increase of liver FABP content, whereas feeding of cholesterol, cholestyramine, mevinolin or cholate caused a marked decrease. The significance of the combined determination of fatty acid-binding capacity and FABP content (by immunochemical quantitation and blotting analysis) is indicated.

Animals↗