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PubMed1996

In vitro antioxidant effects of estrogens with a hindered 3-OH function on the copper-induced oxidation of low density lipoprotein.

Estrogens with some bulky alkyl substituents in both the 2- and 4-positions have been synthesized and evaluated for the ability to inhibit the in vitro oxidation of low density lipoprotein as determined by the thiobarbituric reactive substances method. The present compounds with bulky groups in either the 2- or the 4-position (but not both the 2- and 4-) were especially effective as antioxidants, having IC50 values lower than either estradiol or probucol; however, they do not bind to the estrogen receptor with any great affinities (RBA < 0.1 versus estradiol). This separation of antioxidant efficacy from estrogenicity may allow these compounds to serve as useful probes for ascertaining the relative importance of these effects in the cardioprotective role played by estrogens.

Alkylation↗

PubMed1983

Differential induction of cytosolic epoxide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities.

Three major enzyme systems have been shown to metabolize epoxidized xenobiotics in vertebrate tissues, and this study demonstrates that these enzyme systems can be differentially induced. The cytosolic epoxide hydrolase activity was routinely monitored with trans-beta-ethylstyrene oxide, the microsomal epoxide hydrolase activity with benzo(a)pyrene, 4,5-oxide, and the glutathione S-transferase activity with 2,4-dichloro-4-nitrobenzene. Commonly used inducers of microsomal mixed-function oxidase, microsomal epoxide hydrolase, and cytosolic glutathione S-transferase activities failed to cause significant induction of the cytosolic epoxide hydrolase while leading to the expected induction of the other epoxide metabolizing enzymes. The compounds tested by ip injection into male Swiss-Webster mice included phenobarbital, 3-methylcholanthrene, Aroclor 1254, trans- and cis-stilbene oxides, pregnenolone-16 alpha-carbonitrile, chalcone, and 4-bromochalcone. To determine if there were strain, sex, or species differences, the enzymes were monitored in male C57BL/6 mice, female Swiss-Webster mice, and male Sprague-Dawley rats following ip injection of phenobarbital, 3-methylcholanthrene, and/or pregnenolone-16 alpha-carbonitrile. The time dependence of enzyme induction was followed in Sprague-Dawley rats following trans-stilbene oxide administration. Male Swiss-Webster mice were additionally exposed to dietary alpha-naphthoflavone and 2(3)-tert-butyl-4-hydroxyanisole while male Sprague-Dawley rats were fed 2,6-di-tert-butyl-4-methylphenol. In no case was significant induction of cytosolic epoxide hydrolase activity observed. Dietary di-(2-ethylhexyl)phthalate, 2-ethyl-l-hexanol, and clofibrate proved to be potent inducers of the cytosolic epoxide hydrolase in male Swiss-Webster mice while probucol (a nonperoxisome proliferating hypolipidemic drug) failed to cause significant induction. Data from isoelectric focusing experiments and other data are consistent with the epoxide hydrolase activities induced by 2-ethyl-l-hexanol and clofibrate being due to the same protein that is present in control animals. The lack of induction of the cytosolic epoxide hydrolase by a variety of compounds which were selected to demonstrate induction of other xenobiotic metabolizing enzymes, may indicate that the cytosolic epoxide hydrolase has a constitutive role whereas its induction by clofibrate could be related to some of the pharmacological and/or carcinogenic actions of this drug.

Animals↗

PubMed1994

Vascular permeability in diabetics and implications for therapy.

Several factors contribute to increased vascular permeability in diabetes mellitus, namely hyperglycaemia leading to increased production of diacylglycerol and thence protein kinase C, non-enzymatic glucosylation generating free radicals and lipid peroxides, sorbitol formation, loss of endothelial cell surface heparan sulphates, and the action of arachidonate derivatives that affect endothelial cell contractility. In view of the importance of oxidative damage, serious consideration must be given to therapeutic regimens that utilise vitamin E or ascorbic acid or D-myoinositol. Probucol is an available antioxidant whose properties have received insufficient attention. The oleate of monounsaturated oil diets is likewise anti-oxidant. Furthermore there is a possibility of replacing lost surface heparan sulphates.

Animals↗

PubMed1992

Effect of hypolipidemic drugs on cholinesterase activity in the rat.

1. The effect of four hypolipidemic agents with different mechanisms of action (fenofibrate, probucol, colestipol and nicotinic acid) on plasma and liver cholinesterase has been studied. 2. Liver weight and liver weight/body weight ratio increased only after treatment with fenofibrate. 3. Plasma and liver cholinesterase activity increased markedly after fenofibrate, a strong peroxisome proliferator, and slightly after nicotinic acid, a weak peroxisome proliferator. 4. The data obtained suggest that increased cholinesterase activity is due to increased rate of fatty acid oxidation caused by peroxisome proliferators.

Animals↗

PubMed1991

Cholesterol-rich LDL perfused at physiological LDL-cholesterol concentration induces platelet aggregation and PAF-acetylhydrolase activation.

The aim of this research was to perform an in vivo study on the relationships between lipid oxide (LP), platelet aggregation and PAF-acetylhydrolase in a model using perfusion of cholesterol-rich LDL media diluted to physiological LDL-cholesterol concentration. Normal rabbits were infused with LDL (d 1.025-1.063 g/ml) extracted from rabbits previously fed either with standard food (I-LDL group), 1% cholesterol food (II-LDL group) or 1% cholesterol plus probucol (IV-LDL group). CU2+ modified II-LDL was also infused (III-LDL group). After dilution as above, LP increased significantly in III- and II-LDL media. After perfusion, LP significantly increased in III- and II-LDL groups as compared to baseline values and to control. Compared to the I-LDL group, PAF-acetylhydrolase and platelet aggregation significantly increased in III- and II-LDL groups. These data indicate the property of cholesterol- rich LDL to activate PAF-acetylhydrolase and enhance platelet aggregation, even when perfused through a medium containing a physiological LDL-cholesterol concentration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2005

Suppressive effects of cacao liquor polyphenols (CLP) on LDL oxidation and the development of atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic rabbits.

We investigated the properties of cacao liquor polyphenols (CLP), which have an antioxidative effect on low-density lipoprotein (LDL) and an anti-atherosclerotic effect in the spontaneous familial hypercholesterolemic model, the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit. After 6 months of dietary administration of CLP at 1% (w/w) to the KHC rabbits, a higher total cholesterol concentration was observed in the treatment group compared to the control group. However, no other effects were noted in lipid profiles in plasma or lipoproteins. The plasma concentration of thiobarbituric acid reactive substances (TBARS), which is a lipid-peroxidation index, was significantly decreased 1 month after the start of CLP administration compared to that of the control group. The antioxidative effect of CLP on LDL was observed from 2 to 4 months of administration. The area of atherosclerotic lesions in the aorta in the CLP group (32.01+/-1.58%) was significantly smaller than that in the control group (47.05+/-3.29%), and the tissue cholesterol and TBARS concentrations were lower in the CLP group than in the control group. The anti-atherosclerotic effect of CLP was confirmed both rheologically and histopathologically. An in vitro study using KHC rabbit-derived LDL revealed that CLP significantly prolonged the lag time of LDL oxidation that was induced by a lipophilic azo-radical initiator, 2,2'-azobis(4-methoxy)-2,4-dimethylvaleronitrile (V-70), or Cu(2+) from a low concentration of 0.1 microg/mL. The antioxidative effect of CLP was superior to those of the well-known antioxidative substances, vitamin C, vitamin E and probucol. Therefore, CLP suppressed the generation of atherosclerosis, and its antioxidative effect appeared to have an important role in its anti-atherosclerotic activity.

Animals↗

PubMed2004

Novel 3,5-diaryl pyrazolines and pyrazole as low-density lipoprotein (LDL) oxidation inhibitor.

Compounds 4a-j and 5 were synthesized by cyclocondensation of 3a-j and hydrazine and showed significant LDL-antioxidant activities in the TBARS assay, the lag time of conjugated diene production, the relative electrophoretic mobility (REM) of ox-LDL, the apoB-100 fragmentation, and the macrophage-mediated LDL oxidation. Among compounds 4a-j and 5, 4a was found to be the most active compound as an inhibitor of LDL oxidation and 4a (IC50 = 0.1 microM) was 6-fold more potent than probucol (IC50 = 0.6 microM) in the TBARS assay.

Antioxidants↗

PubMed2006

Importance of acyl-coenzyme A:cholesterol acyltransferase 1/2 dual inhibition for anti-atherosclerotic potency of pactimibe.

Pactimibe sulfate, [7-(2,2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate, a novel Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, was investigated in vitro and in vivo to characterize its potential. Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe. Kinetic analysis revealed pactimibe is a noncompetitive inhibitor of oleoyl-CoA (Ki value: 5.6 microM). Furthermore, pactimibe markedly inhibited cholesteryl ester formation (IC50: 6.7 microM) in human monocyte-derived macrophages, and inhibited copper-induced oxidation of low density lipoprotein more potently than probucol. Pactimibe exerted potent lipid-lowering and anti-atherosclerotic effects in atherogenic diet-fed hamsters. At doses of 3 and 10 mg/kg for 90 days, pactimibe decreased serum total cholesterol by 70% and 72%, and aortic fatty streak area by 79% and 95%, respectively. Despite similar cholesterol lowering, fatty streak area reduction was greater by 10 mg/kg. These results suggest that ACAT1/2 dual inhibitor pactimibe has anti-atherosclerotic potential beyond its plasma cholesterol-lowering activity.

Acyl Coenzyme A↗

PubMed2006

Protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity.

Adriamycin is a potent antitumor drug that is known to cause severe cardiotoxicity. This study examined the protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity. Calceolarioside significantly inhibited the adriamycin induced cell death and caspase-3 activation, which may be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Calceolarioside increased the expression of the antioxidant molecules and decreased the level of intracellular reactive oxygen species. Catalase, glutathione, N-acetylcysteine, Mannitol and Mn-TBAP (manganese (III) tetrakis-(4-benzoic acid) porphyrin) significantly inhibited the H9c2 cell death induced by adriamycin. Calceolarioside significantly inhibited H9c2 cell death, and was more effective than that observed with the other antioxidants, including probucol, ascorbic acid, and alpha-tocopherol. Overall, these results suggest that calceolarioside can inhibit adriamycin-induced apoptosis in H9c2 cardiomyocyte by inhibiting the generation of reactive oxygen species. Calceolarioside may be a potential candidate agent that inhibits cardiomyocyte-toxicity in adriamycin-exposed patients.

Animals↗

PubMed2005

Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability.

Association of a drug with chylomicrons in the enterocyte is an essential step in the lymphatic absorption pathway. In this article, the uptake of lipophilic compounds by chylomicrons ex vivo was compared to the corresponding intestinal lymphatic bioavailability reported in rats in order to elucidate the degree of correlation and to evaluate the utilization of this correlation as a predictive measurement of the lymphatic bioavailability potential of lipophilic drugs. Nine lipophilic compounds (Vitamin D(3), Vitamin E, halofantrine, probucol, diazepam, testosterone, cyclosporin A, benzo[a]pyrene and p,p'-DDT) at a concentration of 1.75 x 10(-6)M were incubated for 1h with chylomicron emulsion separated from rat blood. A strong linear correlation was found between the degree of association of compounds with chylomicrons ex vivo and the lymphatic transport reported in rats (r(2)=0.94, P<0.0001), whereas logP and solubility in long chain triglycerides showed only moderate correlation with lymphatic bioavailability. The linear correlation between the degree of uptake of compounds by isolated chylomicrons and intestinal lymphatic transport suggests that the two processes are governed by similar factors. Thus, the degree of association of lipophilic compounds with isolated chylomicrons can be used as a simple screening model for estimation of intestinal lymphatic transport potential of drug molecules. This approach is important in view of the practical difficulties in direct determination of the lymphatic bioavailability in vivo.

Animals↗

PubMed2006

Tiliroside and gnaphaliin inhibit human low density lipoprotein oxidation.

Two flavonoids, gnaphaliin and tiliroside, isolated from Helichrysum italicum, were studied in vitro for their capacity to inhibit Cu(2+)-induced human low density lipoprotein (LDL) and diluted plasma oxidation. LDL oxidation was monitored by conjugated diene, thiobarbituric acid-reactive substances (TBARS) formation and electrophoretic mobility on agarose gel. Gnaphaliin and tiliroside increased the lag-phase for diene conjugate production in a dose-dependent manner. The reduction of TBARS production confirmed the antioxidant activity of gnaphaliin and tiliroside with 50% inhibitory concentration (IC(50)) values of 8.0+/-3.9 microM and 7.0+/-2.6 microM respectively. Furthermore, the flavonoids negated the Cu(2+)-induced increase in electrophoretic mobility of LDL. Antioxidant activity of gnaphaliin and tiliroside was significantly different when diluted plasma was oxidised by adding 1 mM CuSO(4). Although both flavonoids again reduced the TBARS production, tiliroside showed higher activity than gnaphaliin (IC(50)=10.6+/-2.5 microM vs. IC(50)>50 microM). In conclusion, tiliroside and gnaphaliin are antioxidants against in vitro Cu(2+)-induced LDL oxidation in the same order of magnitude compared to that of the reference drug, probucol.

Benzopyrans↗

PubMed2004

Protective mechanisms against peptide and protein peroxides generated by singlet oxygen.

Reaction of certain amino acids, peptides, and proteins with singlet oxygen yields substrate-derived peroxides. Recent studies have shown that these species are formed within intact cells and can inactivate key cellular enzymes. This study examines potential mechanisms by which cells might remove or detoxify such peroxides. It is shown that catalase, horseradish peroxidase, and Cu/Zn superoxide dismutase do not react rapidly with these peroxides. Oxymyoglobin and oxyhemoglobin, but not the met (Fe3+) forms of these proteins, react with peptide but not protein, peroxides with oxidation of the heme iron. Glutathione peroxidase, in the presence of reduced glutathione (GSH) rapidly removes peptide, but not protein, peroxides, consistent with substrate size being a key factor. Protein thiols, GSH, other low-molecular-weight thiols, and the seleno-compound ebselen react, in a nonstoichiometric manner, with both peptide and protein peroxides. Cell lysate studies show that thiol consumption and peroxide removal occur in parallel; the stoichiometry of these reactions suggests that thiol groups are the major direct, or indirect, reductants for these species. Ascorbic acid and some derivatives can remove both the parent peroxides and radicals derived from them, whereas methionine and the synthetic phenolic antioxidants Probucol and BHT show little activity. These studies show that cells do not have efficient enzymatic defenses against protein peroxides, with only thiols and ascorbic acid able to remove these materials; the slow removal of these species is consistent with protein peroxides playing a role in cellular dysfunction resulting from oxidative stress.

Animals↗

PubMed2005

Determination of DPPH free radical scavenging activity by reversed-phase HPLC: a sensitive screening method for polyherbal formulations.

The colorimetric method of evaluation of antioxidant activity by scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical is with certain shortcomings like failure to indicate antioxidant activity of certain drugs and interference from color pigments of natural products. A specific HPLC method was developed for evaluating the DPPH free radical scavenging activity of commercial polyherbal formulations using a LiChrospher 100 RP-18e column (250 mm x 4 mm, 5 microM). The mobile phase was a mixture of methanol and water (80:20, v/v) pumped at a flow rate of 1 mL/min. The DPPH peaks were monitored at 517 nm. The method was standardized using known antioxidants such as ascorbic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), probucol and alpha-tocopherol. The 50% radical scavenging activity (IC50) determined by the HPLC method correlated well with that of colorimetry. This HPLC method was applied for the estimation of free radical scavenging activity of Silymarin and a few commercial hepatoprotective polyherbal formulations. While the colorimetric method failed to estimate the free radical scavenging activity of polyherbal formulations, HPLC method was free from interferences and was specific. The HPLC method is sensitive and can be used as a quality control tool for the rapid determination of free radical scavenging activity of variety of products including plant extracts, foods, drugs and polyherbal formulations.

Antioxidants↗

PubMed2006

Cloning and expression of human haptoglobin subunits in Escherichia coli: delineation of a major antioxidant domain.

Human plasma haptoglobin (Hp) comprises alpha and beta subunits. The alpha subunit is heterogeneous in size, therefore isolation of Hp and its subunits is particularly difficult. Using Escherichia coli, we show that alpha1, alpha2, beta, and alpha2beta chain was abundantly expressed and primarily present in the inclusion bodies consisting of about 30% of the cell-lysate proteins. Each cloned subunit retained its immunoreactivity as confirmed using antibodies specific to alpha or beta chain. By circular dichroism, the structure of each expressed subunit was disordered as compared to the native Hp. The antioxidant activity was found to be associated with both alpha and beta chains when assessed by Cu(2+)-induced oxidation of low density lipoprotein (LDL). Of remarkable interest, the antioxidant activity of beta chain was extremely potent and markedly greater than that of native Hp (3.5x), alpha chain (10x) and probucol (15x). The latter is a clinically proved potent compound used for antioxidant therapy. The "unrestricted" structure of beta subunit may therefore render its availability for free-radical scavenge, which provides a utility for the future design of a "mini-Hp" in antioxidant therapy. It may also provide a new insight in understanding the mechanism involved in the antioxidant nature of Hp.

Antioxidants↗

PubMedDate not supplied

Sensitivity and specificity of isolated perfused guinea pig heart to test for drug-induced lengthening of QTc.

INTRODUCTION: The purpose of this study was to determine the sensitivity and specificity for predicting the liability of a compound to lengthen QTc using isolated, perfused guinea pig hearts (Langendorff preparation). METHODS: QTc (Fridericia correction) was calculated from bipolar transventricular electrograms. Hearts were exposed to escalating concentrations of 26 compounds thought to lengthen, and 13 compounds thought not to lengthen, QTc in humans. RESULTS: In this preparation, QTc was found to lengthen in 26 of 26 compounds thought to be positive (sensitivity 1.00) and not to lengthen or to lengthen insignificantly in 13 of 13 compounds thought to be negative (specificity 1.0) in man. Probucol and ontazolast could not be studied because of limited solubility. Successful experiments were conducted on over 98% of guinea pigs anesthetized. DISCUSSION: We believe that the isolated perfused guinea pig heart is an in vitro preparation that could be utilized early in preclinical testing for identifying a liability to lengthen QTc in humans, but we do not believe--as is true also for other in vitro methods--that the concentration at which the liability is demonstrated in vitro necessarily predicts the concentration at which a liability exists in man.

Animals↗

PubMed1989

Management of hypercholesterolemia. Approach to diet and drug therapy.

The benefit of lowering elevated plasma low-density lipoprotein cholesterol levels and preventing coronary artery disease is now well documented. The guidelines formulated by the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults provide a rational approach to lipid level management. Once an elevation in low-density lipoprotein cholesterol level has been confirmed in an accurate and precise laboratory, the initial step in therapy remains regulation of diet. Pharmacologic intervention is recommended only if patients do not achieve desirable low-density lipoprotein cholesterol levels after an adequate period receiving regulated diet. The guidelines provide a mix of specific low-density lipoprotein level cutoff points and additional cardiovascular risk factors on which to base decisions in regard to drug therapy. The initial approach should be monotherapy with either a bile acid binding resin or nicotinic acid, with selection based on a variety of factors, including patient age, sex, and the severity and exact type of lipid disorder. Should difficulties or inadequate control occur with either of these agents, the hydroxy-methylglutaryl-coenzyme A reductase inhibitors should be utilized, since their ability to reduce low-density lipoprotein cholesterol levels is significantly greater than that of the other available agents. If inadequate control is obtained with monotherapy, combination therapy is recommended. Optimal combinations of drugs and dosages have yet to be fully assessed and will ultimately depend on patient acceptance, efficacy, side effects, and cost effectiveness. Severely affected subjects may require triple-drug therapy. Other agents, such as fibric acid derivatives and probucol, have only a limited role when elevated low-density lipoprotein cholesterol level is the only abnormality. In patients with combined hyperlipidemias, especially when the very low-density lipoprotein level is significantly increased, the fibrates may even be used for initial therapy.

Adult↗

PubMed2003

Foreign body-type multinucleated giant cell formation is potently induced by alpha-tocopherol and prevented by the diacylglycerol kinase inhibitor R59022.

Multinucleated foreign body giant cells (FBGCs) form by monocyte-derived macrophage fusion on implanted biomedical devices and are believed to mediate oxidative damage to biomaterial surfaces. Our in vitro system of human macrophage culture and interleukin (IL)-4-induced FBGC formation was developed to study the macrophage fusion mechanism and the physiological significance of FBGCs on implanted biomaterials and at other sites of chronic inflammation. Here, we demonstrate that the antioxidant vitamin E (90% alpha-tocopherol) moderately induces macrophage fusion and increases IL-4-induced FBGC formation. Moreover, purified alpha-tocopherol, but not beta-, gamma-, or delta-tocopherol, most remarkably induces macrophage fusion, leading to cultures of confluent FBGCs below normal plasma concentrations. This is not observed with the similar antioxidants probucol or Trolox, suggesting that the alpha-tocopherol effects on FBGC formation are independent of its antioxidant activity. Consistent with the reported activation of diacylglycerol kinase by alpha-tocopherol, the diacylglycerol kinase inhibitor R59022 completely abrogates FBGC formation. R59022 inhibition of IL-4-induced FBGC formation is reversed by alpha-tocopherol, suggesting that FBGC formation involves diacylglycerol kinase activation. This study suggests a novel role for diacylglycerol kinase in the mechanism of macrophage fusion/FBGC formation at sites of chronic inflammation and reveals that the pleiotropic lipophilic compound, alpha-tocopherol, is a highly potent macrophage fusion factor.

Antioxidants↗

PubMed1995

Surgery, drugs, lifestyle, and hyperlipidemia.

Heart disease is the number-one cause of death in the United States, and more money is spent on its treatment each year than for any other condition. Both epidemiologic and experimental data clearly show that elevated plasma cholesterol levels increase the risk of death from coronary heart disease. Genetic insufficiencies can cause high blood cholesterol, but most people with high cholesterol do not have genetic abnormalities; rather, they have lifestyles that include high-fat diets and little exercise. Cholesterol can be managed aggressively with coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, partial ileal bypass, and even liver transplant. Antihyperlipidemic drugs include bile-acid-binding resins, nicotinic acid, fibric acid derivatives, hydroxymethyglutaryl coenzyme A-reductase inhibitors, and the antioxidant probucol. Strict programs of low-fat diets and exercise are also effective for reducing cholesterol, lowering blood pressure, and preventing heart disease without the side effects associated with surgery and drug therapy. Such lifestyle changes are critical to reducing the incidence of heart disease in this country.

Adult↗