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PubMed1998

Isoorientin-6"-O-glucoside, a water-soluble antioxidant isolated from Gentiana arisanensis.

The antioxidant activities of isoorientin-6"-O-glucoside were studied using various models. Isoorientin-6"-O-glucoside was more potent than Trolox, probucol and butylated hydroxytoluene (BHT) in reducing the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). It also scavenged superoxide anion, peroxyl and hydroxyl radicals that were generated by xanthine/xanthine oxidase, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) and Fe3+-ascorbate-EDTA-H2O2 system, respectively. The IC50 value, stoichiometry factor and second-order rate constant were 9.0+/-0.8 microM, 1.8+/-0.1 and 2.6 X 10(10) M(-1) s(-1) for superoxide generation, peroxyl and hydroxyl radicals. However, isoorientin-6"-O-glucoside did not inhibit xanthine oxidase activity or scavenge hydrogen peroxide (H2O2), carbon radical or 2,2'-azobis(2,4-dimethyl-valeronitrile) (AMVN)-derived peroxyl radical in hexane. Isoorientin-6"-O-glucoside inhibited Cu2+-induced oxidation of human low-density lipoprotein (LDL) as measured by fluorescence intensity, thiobarbituric acid-reactive substance formation and electrophoretic mobility. Since isoorientin-6"-O-glucoside did not possess pro-oxidant activity, it may be an effective water-soluble antioxidant that can prevent LDL against oxidation.

Antioxidants↗
PubMed2000

Antioxidative properties of natural coelenterazine and synthetic methyl coelenterazine in rat hepatocytes subjected to tert-butyl hydroperoxide-induced oxidative stress.

Coelenterazine (CLZn; 3, 7-dihydro-2-(p-hydroxybenzyl)-6-(p-hydroxyphenyl)-8-benzylimidazolo++ +[1 ,2-a]pyrazin-3-one), the substrate for bioluminescence reactions in many marine animals, is endowed with high antioxidant properties. This work investigated the antioxidative properties of CLZn in primary cultures of rat hepatocytes subjected to the oxidant tert-butyl hydroperoxide (t-BHP). Micromolar concentrations of CLZn increased survival and decreased lipid peroxidation in rat hepatocytes subjected for 6 hr to 2.5 x 10(-4) M t-BHP. However, the extent of protection was limited by a strong toxicity of CLZn (IC(50) = 6.9 x 10(-5) M). The presence of t-BHP increased the cellular toxicity of CLZn. Methyl coelenterazine (CLZm, 3, 7-dihydro-2-methyl-6-(p-hydroxyphenyl)-8 benzylimidazolo[1, 2-a]pyrazin-3-one), a synthetic analogue of CLZn, demonstrated excellent antioxidant properties, even at very low (3 x 10(-6) M) concentrations and was not toxic throughout most of its effective concentration range. CLZm proved far more effective than reference antioxidants such as Trolox C(R), alpha-tocopherol, BHT, and probucol. The assay of thiobarbituric reactive substances (TBARS) associated with cells and in the culture medium indicated that 10(-5) M CLZm provided a total protection against t-BHP-induced lipid peroxidation. This coelenterazine analogue could be used as a model compound for investigating the action mechanism of imidazolopyrazinones in mammalian hepatocytes.

Animals↗
PubMed2001

Action of the novel antioxidants 4GBE43 and 2BBE43 against lipid peroxidation.

The action and the effect of the newly synthesized compounds 4GBE43 [N-(1,2-diethyltetrahydro-1H-pyrazol-4-yl)-4-[(2E)-3,7-diethyl-2,6-octadienyl] oxybenzamide] and 2BBE43 [2-(benzyloxy)-N-(1,2-diethyltetrahydro-1H-pyrazol-4-yl)benzamide] against lipid peroxidation were studied. 4GBE43 and 2BBE43 quenched the ESR signal of diphenylpicrylhydrazyl (DPPH), suggesting that 4GBE43 and 2BBE43 act as scavengers of free radicals and that each compound quenched 6 free radical molecules. These compounds suppressed the oxidation of methyl linoleate emulsions and soybean phosphatidylcholine liposomes by a free radical initiator, suggesting that these compounds quench the lipid peroxyl radical. 4GBE43 and 2BBE43 also suppressed the spontaneous oxidation of rat brain homogenates. The inhibitory effect of 2BBE43 was of the same order of magnitude (IC50) as that of probucol. The IC50 of 4GBE43 was on the same order of magnitude as that of alpha-tocopherol. However, 4GBE43 at 10(-4)-10(-5) M completely inhibited peroxidation, showing it to be more effective than alpha-tocopherol. These results suggest that 4GBE43 and 2BBE43 act as antioxidants by quenching the lipid peroxyl radical.

Animals↗
PubMed1998

Potent inhibitory activities of hydrophobic aci-reductones (2-hydroxytetronic acid analogs) against membrane and human low-density lipoprotein oxidation.

The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1'-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed. Hepatic microsomal lipid peroxidation was induced by the ascorbate + Fe(II) chemical system. All three agents inhibited membrane lipid peroxidation in a concentration-dependent manner with the order of potency: Trolox (vitamin E) < or = Cpd A << Cpd B < Cpd C; based on the EC50 values, Cpd B and Cpd C were 11- and 19-fold, respectively, more potent than Trolox. In contrast to ascorbic acid, all three agents did not display any membrane prooxidative effect in the presence of iron. When human LDL was incubated with 10 microM of Cu(II), LDL oxidation, determined by the formation of thiobarbituric acid reactive substances, followed a typical sigmoidal curve with an initial lag phase. Preincubation of the LDL samples with low micromolar concentrations (1 and 3 microM) of each agents for 30 min before the addition of copper resulted in significant delays of the lag time of LDL oxidation, and the effectiveness of Cpd B and Cpd C was more prominent than that mediated by either Trolox or probucol. Since clinical evidence strongly supports the hypothesis that atherogenesis is initiated by LDL oxidation, the results suggest that these aryl tetronic acid analogs may serve as promising candidates for future therapeutic use as anti-atherogenic agents.

Animals↗
PubMed2000

Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis.

The prominent role of redox processes in tissue injury and in vascular cell signaling suggest their involvement in the repair reaction to vessel injury, which is a key determinant of restenosis post-angioplasty. Experimental studies showed a protective effect of superoxide dismutase or antioxidants on vasospasm, neointimal thickening or remodeling after balloon injury. It was also shown that oxidized thiols induce chelatable metal-dependent amplification of the vascular repair reaction. Ongoing or completed clinical trials show a promising effect of the antioxidant probucol against restenosis. However, few studies addressed the molecular physiological mechanisms underlying the redox hypothesis of restenosis. We recently showed evidence for marked oxidative stress early after balloon injury, with superoxide production mediated primarily by non-endothelial NAD(P)H oxidase-type flavoenzyme(s). This effect was closely related to the degree of injury. There is evidence supporting a role for such early redox processes in apoptotic cell loss and NF-kappa B activation. We present new data on the time course of oxidative stress after balloon injury of intact rabbit iliac arteries. Our data show that despite substantial neointimal growth and lumen narrowing, superoxide production and glutathione levels are unaltered at day 14 and 28 after balloon injury. At day 7 after injury, the peak neointimal proliferation in this model, there was significant decrease of vascular superoxide dismutase activity, without clear evidence of spontaneous superoxide production. Thus, oxidative stress after injury is likely to be an early transient event, which parallels the inflammatory and proliferative phases of the vascular response. We propose that such early redox processes act as dose-dependent signal transducers of gene programs that affect the final repair.

Angioplasty, Balloon, Coronary↗
PubMed1999

SKP-450 inhibits migration and DNA synthesis stimulated by oxidized low density lipoprotein in smooth muscle cells.

This study was carried out to examine the inhibitory effects of SKP-450 (2-[2"(1", 3"-dioxolone)-2-methyl]-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1-be nzo pyran), a potassium channel opener, on the proliferation and migration stimulated by oxidized low density lipoprotein (LDL) of cultured smooth muscle cells of Wistar Kyoto rat aorta. SKP-450 (10(-7) and 10(-6) M) as well as probucol (10(-7)-10(-5) M) reduced the production of thiobarbituric acid reactive substances from LDL submitted to CuSO(4) (10 microM). The increased [3H]thymidine incorporation and migration (chemotactic and wound-edge) of the cultured smooth muscle cells in association with increased production of platelet-derived growth factor (PDGF)-BB-like immunoreactivity stimulated by oxidized LDL were significantly reduced by SKP-450 (10(-7)-10(-6) M). Inhibition by SKP-450 of the oxidized LDL-stimulated [3H]thymidine incorporation was antagonized by iberiotoxin (10(-7) M), but not by glibenclamide (10(-6) M), suggestive of mediation of Ca(2+)-activated K(+) channel opening in the action of SKP-450. Taken together, SKP-450 inhibited the proliferation and migration of the smooth muscle cells as well as PDGF production stimulated by oxidized LDL, accompanying with its antiperoxidative action.

Animals↗
PubMed1997

Minimal oxidation and storage of low density lipoproteins result in an increased susceptibility to phospholipid hydrolysis by phospholipase A2.

In vitro-studies have shown that phospholipid hydrolysis of low density lipoproteins (LDL) by bee venom or porcine pancreatic phospholipase A2 (PLA2) leads to an increased uptake of these lipoproteins by macrophages transforming them into foam cells. Recently, a secretory phospholipase A2, group II, was detected in human atherosclerotic plaques. In order to investigate the role of this enzyme in the pathogenesis of atherosclerosis, a structurally identical human secretory PLA2 was purified from the medium of HepG2 cells stimulated with interleukin-6 and tumor necrosis factor-alpha. The activity of the purified enzyme towards the phospholipids of native and modified low density lipoproteins was compared with the activity towards Escherichia coli-membranes and other phospholipid substrates. Compared to E. coli-membranes, native LDL proved to be a poor substrate for group II PLA2. After mild oxidation induced by copper ions or by 2,2-azobis(2-amidinopropane) (AAPH), the susceptibility of LDL to phospholipid hydrolysis was found to be increased by 25 and 23%, respectively, whereas extensive copper-mediated oxidation caused a decreased hydrolysis. Aging of LDL at 6 degrees C for weeks or at 37 degrees C for hours resulted in an increase in PLA2-catalyzed phospholipid hydrolysis of up to 26-fold. LDL protected from oxidation by probucol during aging showed a lesser increase in susceptibility to phospholipid hydrolysis. Our results suggest that PLA2, group II, can increase the atherogenicity of LDL by its ability to hydrolyze the phospholipids of these lipoproteins, especially after modifications that are likely to occur in vivo.

Cell Line↗
PubMed1998

Human cardiac microvascular and macrovascular endothelial cells respond differently to oxidatively modified LDL.

Oxidation of low density lipoproteins (LDL) is considered a key event in the pathogenesis of atherosclerotic lesions. Disturbed generation of coagulatory and anticoagulatory factors by endothelial cells contributes to thrombosis and the progression of atherosclerosis in coronary arteries. In this study, the effects of native LDL (n-LDL) and oxidized LDL (ox-LDL) on human coronary endothelial cells were measured. The reaction of coronary endothelial cells to LDL were compared with those of cardiac microvascular endothelial cells grown under comparable conditions. LDL was isolated by ultracentrifugation and copper oxidized. The degree of oxidation was expressed as malondialdehyd (MDA) equivalents and was 0.78+/-0.14 nM MDA/mg LDL for native LDL and 13.63+/-1.18 nmol MDA/mg LDL for ox-LDL. Basal secretion of t-PA and PAI-1 activity were higher in macrovascular endothelial cells. Incubation of n-LDL in concentrations ranging from 3 to 100 microM/ml LDL-protein did not change t-PA-secretion, PAI-1 activity or procoagulant activity in both cell types. Ox-LDL (3 to 100 microM/ml LDL protein) decreased t-PA secretion in a concentration dependent manner from 30.9+/-1.7 to 13.7+/-30 ng/ml per 24 h per 10(6) cells (P < 0.01), increased PAI-1 antigen from 2772+/-587 to 4441+/-766 ng/ml per 24 h per 10(6) cells (P < 0.05) as well as PAI-1 activity from 34+/-6 to 55+/-9 AU/ml per 24 h per 10(6) cells (P < 0.05) in macrovascular endothelial cells but had only minor effects on microvascular endothelial cells. Procoagulant activity measured as coagulation time, similarly increased only in macrovascular endothelial cells from 197+/-6 to 76+/-6 s/24 h per 10(6) cells (P < 0.05). The effect on PAI-1 secretion showed a dependency to the degree of oxidation and could be completely blocked by the antioxidant probucol. The angiotensin converting enzyme (ACE), which represents an endothelial enzyme not related to coagulation, remained unchanged during incubation with ox-LDL. Basal ACE activity was higher in microvascular endothelial cells. The higher susceptibility of macrovascular endothelial cells to ox-LDL may partially determine the localization of thrombus formation and the development of atherosclerotic plaques in hyperlipidemic patients.

Antioxidants↗
PubMed1998

LDL oxidation: therapeutic perspectives.

The peroxidation step of lipid transormation is considered to be essential in the pathogenesis of atherosclerosis. Although data concerning the mechanisms by which lipid peroxidation occurs in vivo are scarce, several lines of evidence suggest that some endogenous and exogenous compounds with antioxidant activity could have some beneficial effects in the prevention of atherosclerosis. Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) act as the most important hydrophilic and lipophilic antioxidants, respectively in vivo. Accordingly, animal and human studies suggest that these compounds may have some preventive effect against the development of clinical coronary heart disease. Many plant phenols and flavonoids may be important dietary antioxidants and it has been speculated that these compounds in red wine or in the Mediterranean diet could explain the 'French paradox'. Several studies show that antioxidants such as probucol and butylated hydroxytoluene can inhibit development of atherosclerotic lesions in Watanabe and cholesterol-fed rabbits. Some drugs such as beta-blockers, calcium antagonists, hypolipodemic drugs,...appear to have at least in vitro antioxidant effects but the clinical relevance of these properties remains unkonwn. Moreover, some interventions aimed to decrease the LDL-oxidative susceptibility have not been shown to attenuate atherogenesis when cholesterol levels remain markedly elevated.

Animals↗
PubMed1998

The role of (E)-4-hydroxy-2-nonenal in platelet activation by low density lipoprotein and iron.

(E)-4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the oxidation of low density lipoprotein (LDL) which increases the platelet aggregation response to various agonists. HNE formation was increased during the enhanced platelet aggregation to thrombin, ADP. A23187 and epinephrine in the presence of LDL. The increase in platelet aggregation and HNE formation by LDL was inhibited by superoxide dismutase and catalase, suggesting superoxide and hydrogen peroxide produced by platelets during aggregation may be at least partly responsible. The responsiveness of platelets to LDL and the accompanying HNE formation was increased further in the presence of ferrous ion. The effect of ferrous ion on both platelet responses and HNE formation was decreased by superoxide dismutase, catalase and the antioxidants dipyridamole and probucol implicating platelet-derived free radicals. Ferrous ion caused an increase in the release of arachidonic acid from platelet membrane phospholipids in the presence of LDL which was probably caused by increased HNE production. The results suggest iron could increase platelet reactivity at sites of vascular injury by increasing HNE formation and promote the development of atherosclerotic lesions.

Adenosine Diphosphate↗
PubMed2003

NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy.

Cardiac hypertrophy is an adaptive response to increases in blood pressure. Recent studies indicate that the hypertrophic process is associated with increases in intracellular oxidative stress in cardiomyocytes. We hypothesize that superoxide anion mediates the hypertrophic response and that antioxidant therapy may be effective in attenuating cardiac hypertrophy. Neonatal rat cardiac myocytes were stimulated with angiotensin II (AngII, 1 microM) with and without various antioxidants. N-acetylcysteine (NAC, 10 mM) and probucol (50 microM), and to a lesser extent, vitamin C (500 microM) and reduced glutathione (1 mM), inhibited AngII-induced [(3)H]-leucine uptake and atrial natriuretic factor (ANF) promoter activity. The hypertrophic response is mediated by superoxide anion (O(2)(-).) since cell-permeable polyethylene glycol (PEG)-conjugated superoxide dismutase (50 U/ml), but not PEG-catalase (500 U/ml), attenuated AngII-induced [(3)H]-leucine uptake and ANF promoter activity. Furthermore, NAC blocked AngII-induced increase in myocardial oxidative stress, decreased the expression of ANF and myosin light chain-2v, and inhibited the re-organization of cytoskeletal proteins, desmin and alpha-actinin. These effects of AngII were abolished by angiotensin type 1 receptor blocker, losartan, but not type 2 receptor blocker, PD123319. Indeed, co-administration of losartan (10 mg/kg/d, 14 d) or NAC (200 mg/kg/d, 14 d) inhibited AngII-induced O(2)(-). production and cardiac hypertrophy in rats without affecting blood pressure. These findings indicate that the generation of O(2)(-). contributes to oxidant-induced hypertrophic response and suggest that antioxidant therapy may have beneficial effects in cardiac hypertrophy.

Angiotensin II↗
PubMed1995

Coronary artery bypass grafting in familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disorder caused by a mutation of the gene for the low-density lipoprotein receptor and is characterized by rapidly progressing coronary atherosclerosis. We assessed the long-term results of coronary artery bypass grafting performed during the past 13 years in 62 patients with heterozygous familial hypercholesterolemia, whose mean plasma total and low-density lipoprotein cholesterol level was 327 mg/dl, respectively. The patients had severe coronary atherosclerosis, with coronary stenosis index of 19.7, and the prevalence of extracoronary atherosclerotic lesions was 27%. Sixty-one patients underwent successful coronary artery bypass operation, with an average of 2.5 grafts, and the coronary stenosis index decreased to 7.1. After operation, all patients consumed a cholesterol-lowering diet and received drug therapy with pravastatin, probucol, or cholestyramine. Seven patients who were resistant to drug therapy were treated with plasma low-density lipoprotein apheresis. The cholesterol-lowering therapy reduced plasma total cholesterol level by 37%, low-density lipoprotein cholesterol level by 42%, and low-density lipoprotein/high-density lipoprotein cholesterol ratio by 37% (p < 0.001). During the follow-up period (mean, 52 months; range, 10 to 157 months), there was no cardiac death, but three patients died of malignant disease. The actuarial survival rate was 95% at 5 years and 89% at 12 years after operation. The actuarial freedom from recurrent angina was 90% at 5 years and 53% at 11 years after operation. Four patients underwent reoperation, an average of 8 years postoperatively, because of vein graft atherosclerosis. In spite of severe coronary atherosclerosis, these patients with familial hypercholesterolemia showed good long-term outcome after coronary artery bypass operation. The present findings suggest that aggressive use of arterial grafts, intensive cholesterol-lowering drug therapy, and low-density lipoprotein apheresis may be useful in patients with familial hypercholesterolemia.

Actuarial Analysis↗
PubMed1999

Intracellular generation of MDA-LYS epitope in foam cells.

Oxidative stress plays a central role in atherogenesis. Antioxidants, such as probucol, inhibit oxidation of LDL, retard secretion of interleukin-1, growth factors and chemoattractants, and thus inhibit progression of atherosclerosis. Other antioxidants with an ability to inhibit LDL oxidation, however, could not prevent progression of atherosclerosis. The inconsistency between antioxidant potencies indicated oxidative events might have occurred at locations other than LDL. MDA-lysine epitope (MDA-lys) is closely associated with atherogenesis and was recognized as marker for oxidation. We traced formation of MDA-lys during oxidation of LDL and formation of foam cells. The results indicated that thiobarbituric acid reactive substance (TBARS) was primarily present in lipid fraction of ox-LDL not associated with protein fraction after Cu2+ oxidation in vitro. Oxidized LDL did not increase significant immunoreactivity of MDA-lys epitope under our experimental conditions. Foam cells, however, showed the presence of MDA-lys epitope suggesting that intracellular oxidation events occurred to internalized lipids. The uptake of non-oxidatively modified LDL (acetylated LDL) was sufficient to generate MDA-lys epitope in foam cells, consistent with the hypothesis that atherosclerosis is associated with oxidative events in addition to LDL oxidation. We hypothesized that MDA-lys may be generated through intracellular lipid metabolism during the formation of foam cells.

Animals↗
PubMed2002

Effects of antioxidants on kidney disease.

Kidney mesangial cells (MCs) and vascular smooth muscle cells (VSMCs) are closely related in terms of origin, microscopic anatomy, histochemistry, and contractility. This relationship suggests a similarity between kidney glomerular sclerosis and atherosclerosis. Vitamin E appears beneficial in the prevention and treatment of coronary disease and also inhibits the proliferation of VSMCs in vitro. We used vitamin E and probucol to treat glomerular sclerosis and MC-proliferative glomerulonephritis (GN) in two animal models of glomerular disease. Using rats, a remnant kidney model accelerated with hyperlipidemia was employed to reflect progressive glomerular sclerosis leading to chronic renal failure, and an anti-thymocyte serum treatment was used to model acute MC-proliferative GN. Supplemental dietary antioxidants suppress MC proliferation and glomerular sclerosis in models of glomerular disease in rats. These results suggest that treatment with antioxidants may be a promising intervention to prevent progression of kidney disease.

Animals↗
PubMed1995

Clinical trials of antioxidants in atherosclerosis: are we doing the right thing?

The hypothesis that oxidative modification of low density lipoprotein contributes to the progression of atherosclerosis is supported by an impressive body of in-vitro findings and by persuasive results in animal models of atherosclerosis. The hypothesis was originally proposed specifically to account for foam cell formation but oxidation of LDL has now been shown to confer on it a long list of new biological properties any one of which could in principle enhance its atherogenicity. The relative importance of these altered biological properties in vivo remains uncertain. Whatever the precise mechanisms, we know that antioxidants can slow the atherogenic process in several experimental models, including LDL-receptor-deficient rabbits, cholesterol-fed rabbits, and cholesterol-fed non-human primates. Of 18 published studies, 13 have given strongly positive results, the rate of progression of lesions being reduced by 50-80%; 2 have yielded marginally positive results; and 3 have been negative (see ref 3 for references). Furthermore, the fact that four different antioxidant compounds have been used--probucol, butylated hydroxytoluene, N,N'-diphenyl-phenylenediamine, and vitamin E--supports the conclusion that they are working via the property they all share, namely, their antioxidant potential.

Animals↗
PubMed2000

Restenosis: a challenge for pharmacology.

The quest for an anti-restenotic drug continues to be a major challenge in the field of cardiovascular pharmacology because most therapies with proven efficacy in experimental neointima models have failed to limit restenosis. Some drug classes, including glycoprotein IIb/IIIa antagonists, nitric oxide donors and the antioxidant probucol, have recently demonstrated potential benefits in clinical trials. Progress in the development of local delivery systems for administration of drugs, antisense oligonucleotides or genes, in combination with an improved understanding of the pathogenesis of restenosis holds promise for ultimate pharmacotherapy of this condition.

Angioplasty, Balloon, Coronary↗
PubMed1999

Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes.

Reactive oxygen species (ROS) are elevated by metabolic changes in diabetes, including autoxidation and increased advanced glycation. Endogenous protection by the glutathione redox cycle is also compromised by the competing NADPH requirement of elevated polyol pathway flux. Antioxidant treatment strategies prevent or reverse nerve conduction velocity (NCV) deficits in diabetic rats. These include lipophilic scavengers such as butylated hydroxytoluene, probucol and vitamin E, more hydrophilic agents like alpha-lipoic acid and acetyl cysteine, and transition metal chelators that inhibit autoxidation. In the long-term, elevated ROS cause cumulative damage to neurons and Schwann cells, however, they also have a deleterious effect on nerve blood flow in the short term. This causes endoneurial hypoxia, which is responsible for early NCV deficits. Antioxidant treatment corrects the blood flow deficit and promotes normal endoneurial oxygenation. ROS cause antioxidant-preventable vascular endothelium abnormalities, neutralizing nitric oxide mediated vasodilation and increasing reactivity to vasoconstrictors. Unsaturated fatty acids are a major target for ROS and essential fatty acid metabolism is impaired by diabetes. Gamma-linolenic acid stimulates vasodilator prostanoid production, and there are marked synergistic interactions between gamma-linolenic acid and antioxidants. This has encouraged the development of novel drugs such as ascorbyl-gamma-linolenic acid and gamma-linolenic acid-lipoic acid with enhanced therapeutic potential.

Animals↗
PubMed1993

Peroxisome proliferators as inducers and substrates of UDP-glucuronosyltransferases.

Peroxisome proliferators, despite their chemically unrelated structures, share the common property of being able to stimulate the glucuronidation of bilirubin in rodents and, probably, also in man. The aryloxycarboxylic acids (clofibric acid, fenofibrate, bezafibrate, ciprofibrate), tiadenol and probucol, all of which have hypolipidemic properties, as well as the fatty acid-like perfluorodecanoic acid all enhanced the expression of the UDP-glucuronosyltransferase (UGT) form involved in the conjugation of the pigment. This induction is manifested by an increase in the mRNA species encoding the protein with a subsequent increase in the neosynthesis of the corresponding protein in the endoplasmic reticulum. The induction process is concomitant with that of cytochrome P-450-IVA1 and cytosolic epoxide hydrolase, which, like bilirubin UGT, are mainly involved in the metabolism of endogenous substrates. With a series of carboxylic acids related to clofibric acid, it was possible to demonstrate that induction was mediated via specific interactions based on the physicochemical properties of the inducers. Until now, the molecular basis of induction of bilirubin UGT is not known. The peroxisome poliferators that possess a carboxyl group are good substrates of UGT, especially in man. The acylglucuronides formed are known for their instability and reactivity which could contribute to the toxicity encountered in some patients treated with the drugs. There is convincing evidence that UGT bilirubin does not catalyze the glucuronidation of these substances even if the two types of substrate form acylglucuronides.

Animals↗