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PubMed2004

Probucol inhibits ABCA1-mediated cellular lipid efflux.

OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of lipids from cells to lipid-poor apolipoproteins. In this article, we characterize the effect of probucol on cellular ABCA1-mediated lipid efflux. METHODS AND RESULTS: Probucol inhibited cholesterol efflux up to 80% in J774 macrophages expressing ABCA1. In Fu5AH hepatoma cells that contain scavenger receptor class B, type I, but not functional ABCA1, we observed no effect of probucol on cholesterol efflux. Probucol inhibited cholesterol efflux from normal human skin fibroblasts but not from fibroblasts from a Tangier patient. Fluorescent confocal microscopy and biotinylation assay demonstrated that in J774 cells probucol impaired the translocation of ABCA1 from intracellular compartments to the plasma membrane. Probucol also inhibited the formation of an ABCA1-linked cholesterol oxidase sensitive plasma membrane domain. Consistent with the inhibitory effect on ABCA1 translocation to the plasma membrane, probucol reduced cell surface-specific [125I]-labeled apolipoprotein-AI binding. CONCLUSIONS: We conclude that probucol is an effective inhibitor of ABCA1-mediated cholesterol efflux without influencing scavenger receptor class B type I-mediated efflux. The inhibition of ABCA1 translocation to the plasma membrane may in part explain the reported in vivo high-density lipoprotein-lowering action of probucol.

ATP Binding Cassette Transporter 1↗

PubMed2005

Probucol enhances the expression of human hepatic scavenger receptor class B type I, possibly through a species-specific mechanism.

OBJECTIVE: Scavenger receptor class B type I (SR-BI) is a major receptor for high-density lipoproteins (HDL) in the liver, which is the terminus of reverse cholesterol transport. Overexpression of SR-BI attenuated experimental atherosclerosis in murine models, concomitant with a reduction in plasma HDL-cholesterol levels. Probucol is known to be a potent hypolipidemic drug to regress xanthoma formation and carotid atherosclerosis in conjunction with a marked reduction in HDL-cholesterol levels. The aim of the present study was to know the effect of probucol on the expression of SR-BI and the underlying mechanism. METHODS AND RESULTS: We found that probucol increased the expression of SR-BI proteins in in vitro human liver cells and an in vivo rabbit model, but not in wild-type C57Bl6 mice. The decay curve of SR-BI protein was markedly retarded in probucol-treated HepG2 cells in the presence of cycloheximide, indicating that probucol may stabilize human SR-BI protein. To determine the underlying mechanism for the observed species-specific effect, we conducted the following host-swap experiments, in which SR-BI was transfected or expressed in heterologous cells or hosts. Probucol did not increase human SR-BI protein in the liver of transgenic mice carrying the entire human SR-BI genome. Although probucol could stabilize even murine SR-BI, when transfected into a human cell line, HepG2, human SR-BI was not stabilized in a mouse hepatoma cell line, Hepa 1-6, treated with probucol. CONCLUSIONS: Probucol enhances hepatic SR-BI protein expression, possibly through species-specific stabilization of the protein.

Adult↗

PubMed1997

Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis.

Probucol is a potent inhibitor of atherosclerosis in animal models. However, the mechanism of its antiatherogenic effect is not known. To investigate the effects of probucol on gene expression of VCAM-1, MCP-1, and M-CSF in vivo during the early stages of atherogenesis, we determined gene expression in 12 control WHHL rabbits and 12 WHHL rabbits fed 1% probucol from age 3 weeks. Three animals from each group were killed at 6, 9, 12, and 18 weeks of age. Two intimal/medial segments of the thoracic aorta, each comprising the orifices of a pair of intercostal arteries, were analyzed by semiquantitative RT-PCR using GAPDH as an internal standard. A third segment located between these two segments was studied by immunocytochemistry. A basal level of VCAM-1 gene expression was observed in lesion-free aortas of both treated and untreated WHHL rabbits (and in normal NZW aortas). Immunocytochemistry showed some VCAM-1 protein in normal arteries and confirmed that VCAM-1 protein expression generally correlated with gene expression. In the untreated WHHL rabbits, a marked upregulation of VCAM-1 expression was observed at 18 weeks. To correlate gene expression with intimal monocyte/macrophages in each animal, the macrophage area was determined by morphometry of immunostained sections. In addition, a scoring system of lesions was used. VCAM-1 expression showed a highly significant correlation with the extent of intimal macrophage presence (P < .001). A lesser degree of correlation between gene expression and macrophage accumulation was also seen for MCP-1. In contrast, M-CSF expression remained constant over the entire study period and showed no correlation with the intimal macrophage accumulation. Probucol treatment completely prevented lesion formation in all animals up to 18 weeks of age. Probucol reduced the level of basal VCAM-1 expression and prevented its upregulation. MCP-1 expression was not affected by probucol treatment, whereas M-CSF expression was significantly lowered by probucol. Our results support the idea that VCAM-1 plays an important role in early atherogenesis and suggest that the antiatherogenic effect of probucol may in part be due to a downregulation of VCAM-1. Reduction of the basal level of M-CSF gene expression by probucol treatment may also contribute to its ability to inhibit atherogenesis.

Animals↗

PubMed1999

Probucol enhances selective uptake of HDL-associated cholesteryl esters in vitro by a scavenger receptor B-I-dependent mechanism.

Recently, the class B, type I scavenger receptor (SR-BI) has been shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters (CEs), ie, lipid uptake independent of HDL holoparticle uptake. In vivo, this selective uptake delivers CEs to the liver for excretion and to steroidogenic tissues for hormone synthesis. Probucol, a hydrophobic antioxidant drug, lowers plasma cholesterol in humans and rodents and may inhibit progression of atherosclerosis and postangioplasty restenosis. In this study, the effect of probucol on HDL selective CE uptake was investigated in mice and in cells expressing SR-BI. Probucol feeding lowered plasma HDL cholesterol and markedly increased selective CE uptake from HDL in the liver and adrenal glands. However, probucol did not alter SR-BI protein levels in membranes from these organs. When incubated with control Chinese hamster ovary (CHO) cells, HDL isolated from probucol-treated mice (P-HDL) and HDL from control mice (C-HDL) showed similar low selective uptake of CEs. However, when incubated with SR-BI-transfected CHO cells, P-HDL showed a 2-fold increase in selective uptake compared with C-HDL. In an adrenal cell line (Y1-BS1), which expresses SR-BI in an adrenocorticotropic hormone-inducible manner, P-HDL showed significantly greater selective CE uptake than did C-HDL, and the differential response was amplified by adrenocorticotropic hormone treatment. In contrast to P-HDL, incorporation of this compound into HDL in vitro did not result in stimulation of selective CE uptake by SR-BI-transfected CHO cells, even though a significant mass of probucol could be detected in the HDL preparation. The specific interaction of P-HDL with SR-BI in cell culture could be observed after only 24 hours of probucol feeding, when there were minimal changes in HDL size and composition. Thus, probucol or one of its metabolites increases selective CE uptake in vivo by modifying HDL in a way that causes enhanced interaction with SR-BI. The increased interaction of P-HDL with SR-BI in the liver and arterial wall may be partly responsible for the effects of probucol on atherosclerosis and restenosis.

Administration, Oral↗

PubMedDate not supplied

Probucol does not affect lipoprotein metabolism in macrophages of Watanabe heritable hyperlipidemic rabbits.

We recently reported that the antioxidant action of probucol inhibited the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. In this study, we investigated another possible action of probucol: its action as an antiatherogenic agent on macrophages. When WHHL rabbit peritoneal macrophages were pre-incubated in vitro with probucol and then incubated with several atherogenic lipoproteins, the incorporation of the lipoproteins was not significantly prevented. In the case of mouse peritoneal macrophages, pre-incubation with probucol showed slight, although not statistically significant, changes in the amount of lipoprotein incorporations. We also used macrophages obtained from mice and WHHL rabbits fed with probucol, but the amount of uptake of lipoproteins by these cells was not less than that by control macrophages. Furthermore, to investigate the incorporation of atherogenic lipoproteins into these cells, we prepared probucol-containing macrophages; however, probucol in macrophages failed to prevent the uptake of such lipoproteins. In conclusion, probucol did not prevent foam cell transformation of macrophages of WHHL rabbit or mice directly, and the effect of probucol against atherogenesis in WHHL rabbits was due mainly to its inhibitory effect on the oxidative modification of low density lipoprotein, as previously reported.

Animals↗

PubMed2003

Effects of AGI-1067 and probucol after percutaneous coronary interventions.

BACKGROUND: AGI-1067, a metabolically stable modification of probucol, is an equipotent antioxidant to probucol but is pharmacologically distinct. In a multicenter trial, we studied whether AGI-1067 reduces restenosis assessed by intravascular ultrasound (IVUS) after percutaneous coronary intervention (PCI) compared with placebo and probucol used as a positive control. METHODS AND RESULTS: Two weeks before PCI, 305 patients were randomly assigned to 1 of 5 treatment groups: placebo, probucol 500 mg BID, or AGI-1067 70, 140, or 280 mg once daily. Patients were treated for 2 weeks before and 4 weeks after PCI. Baseline and 6-month follow-up IVUS were interpreted by a blinded core laboratory. Stents were used in 85% of patients. Luminal area at the PCI site at follow-up was 2.66+/-1.58 mm2 for placebo, 3.69+/-2.69 mm2 for probucol, 2.75+/-1.76 mm2 for AGI-1067 70 mg, 3.17+/-2.26 mm2 for AGI-1067 140 mg, and 3.36+/-2.12 mm2 for AGI-1067 280 mg (P=0.02 for the dose-response relationship; P< or =0.05 for AGI-1067 280 mg and probucol versus placebo). There was a mean narrowing of 5.3 mm3 of reference segment lumen in the placebo group and an enlargement in the AGI-1067 140- and 280-mg groups at follow-up (P=0.05 for 140 mg). An increase in QTc interval >60 ms occurred in 4.8% of placebo patients, 17.4% of probucol patients, and 4.8%, 2.4%, and 2.5% of patients in the AGI-1067 groups (P=0.02). CONCLUSIONS: AGI-1067 and probucol reduce restenosis after PCI. In contrast to probucol, AGI-1067 did not cause prolongation of the QTc interval and improved lumen dimensions of reference segments, suggestive of a direct effect on atherosclerosis.

Angioplasty, Balloon, Coronary↗

PubMed1994

Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. I. Is the extent of atherosclerosis related to resistance of LDL to oxidation?

Lipoprotein oxidation is believed to play an important role in atherogenesis. To investigate whether inhibition of oxidation of low density lipoprotein (LDL) would alter atherogenesis in the nonhuman primate, we administered probucol, a potent antioxidant, to Macaca nemestrina fed a high-fat, high-cholesterol diet. Probucol was administered to half of the 16 monkeys 14 wk after starting the hypercholesterolemic diet, and was given daily until they were sacrificed after 11 mos. To evaluate the antioxidant effect of probucol, the resistance of isolated plasma LDL to in vitro oxidation was evaluated. Probucol significantly increased the resistance of LDL to oxidative modification, as shown by an increase in the lag time required for conjugated diene formation. Lesions in the probucol-treated animals appeared less mature, and increased accumulation of lipid was observed in smooth muscle cells. Comparison of all control and probucol-treated monkeys demonstrated that intimal lesion areas in the thoracic aortas of the probucol-treated monkeys were reduced by 43% (P < 0.0001), but no significant difference in lesion area was found in the abdominal aortas or in the iliac arteries. However, the lag phase of conjugated diene formation was not prolonged in 2 of the 8 probucol-treated animals. A plot of intimal lesion size versus lag phase of all 16 animals showed a trend that lesion size was inversely related to oxidation resistance for all anatomic sites. The strong inverse relationship between intimal lesion size and resistance of LDL to oxidation supports a role for lipoprotein oxidation in the development and progression of lesions of atherosclerosis. The possibility that some of the effect is due to other biological properties of probucol cannot be ruled out.

Animals↗

PubMed2006

Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat.

Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1992

Synergistic interaction between the probucol phenoxyl radical and ascorbic acid in inhibiting the oxidation of low density lipoprotein.

Chain-breaking antioxidants such as butylated hydroxytoluene, alpha-tocopherol, and probucol have been shown to decrease markedly the oxidative modification of low density lipoprotein (LDL). Their mechanism of action appears to involve scavenging of LDL-lipid peroxyl radicals. The purpose of this study was to investigate the occurrence of radical reactions produced during oxidation of LDL and LDL-containing probucol initiated by lipoxygenase or copper. In addition, we have investigated the possibility of a synergistic interaction between ascorbate and probucol in inhibiting the oxidation of LDL. Incubation of LDL-containing probucol and lipoxygenase produced a composite electron spin resonance (ESR) spectrum due to the endogenous alpha-tocopheroxyl radical and probucol-derived phenoxyl radical. The spectral assignment was further verified by chemical oxidation of alpha-tocopherol and probucol. In the presence of ascorbic acid, these radicals in the LDL particle were reduced to their parent compounds with concomitant formation of the ascorbate radical. In both the peroxidation of linoleic acid and the copper-initiated peroxidation of LDL, the antioxidant activity of probucol was significantly increased by low (3-6 microM) concentrations of ascorbate. The probucol-dependent inhibition of LDL oxidation was enhanced in the presence of ascorbic acid. We conclude that the reaction between the phenoxyl radical of probucol and ascorbate results in a synergistic enhancement of the antioxidant capacity of these two compounds and speculate that such reactions could play a role in maintaining the antioxidant status of LDL during oxidative stress in vivo.

Analysis of Variance↗

PubMed1992

Modulation of the physical state of cellular cholesteryl esters by 4,4'-(isopropylidenedithio)bis(2,6-di-t-butylphenol) (probucol).

The effect of 4,4'-(isopropylidenedithio)bis(2,6-di-t-butylphenol) (probucol) on cholesteryl ester physical state was examined in dry mixtures, phospholipid-containing dispersions, and cells. Probucol has little effect on the solid to isotropic transition of cholesteryl oleate, but broadens and decreases the enthalpy of the liquid-crystalline transitions at concentrations as low as 1-2 mol %. A probucol transition is only observed at concentrations greater than 20 mol %. The mesomorphic phases of the cholesteryl oleate/probucol mixtures were identified by visual inspection and polarized light microscopy. Mixtures are liquid at probucol concentrations in excess of 5 mol % at 37 degrees C. Probucol also dramatically reduces the enthalpy of the liquid-crystalline transitions of the cholesteryl oleate core of dispersions of the ester with phospholipids at a concentration of 10 mol %, reducing the enthalpy by greater than 80% and the transition temperatures by approximately 2 degrees C. The phase state of cholesteryl esters in Fu5AH rat hepatoma cells was examined after incubation with cholesterol/phospholipid dispersions that caused the accumulation of anisotropic cholesteryl ester droplets. Differential scanning calorimetry scans of cells incubated with cholesterol-rich phospholipid dispersions indicated a phase transition near 48 degrees C, which was abolished when the cells were co-incubated with 50-100 micrograms/ml of probucol in the loading medium. Subsequent to the formation of isotropic cholesteryl ester droplets in the presence of probucol, the rate of efflux of cholesterol from the cells to phosphatidylcholine-containing acceptors in the medium was increased. These data show that probucol is relatively soluble in cholesteryl esters and that probucol changes the phase state of cholesteryl ester droplets in cells to a more fluid phase in which the cholesteryl esters are more readily mobilized.

Animals↗

PubMed1998

[A comparison of the hypolipidemic action of probucol at doses of 500 and 1000 mg/day in moderate hyperlipoproteinemia].

AIM: Evaluation of effectiveness of hypolipidemic action of probucol in doses 500 and 1000 mg/day and comparison of probucol blood concentrations on the treatment month 3 and 6. MATERIALS AND METHODS: Probucol (Akrikhin, Russia) was given to 41 patients with primary hypercholesterolemia in a dose 500 mg/day. 3 months later the patients were divided into two groups. Group 1 patients exhibited a > 10% decrease in cholesterol levels and continued to take probucol in the dose 500 mg/day. Group 2 patients were crossed over to higher cholesterol dose--up to 1000 mg/day. Lipids levels were measured by enzyme tests, apoproteins--by immunoturbidimetry and immunodiffusion, probucol concentrations--by high-performance liquid chromatography. RESULTS: After 3 months of treatment, cholesterol lowered by 14.3 and 9.2% in groups 1 and 2, respectively. After 6 months, by 19.7 and 12.9%, respectively. Probucol concentrations in blood were higher after 6 months of treatment than after 3 months in both groups. No significant differences existed between the groups by probucol concentrations in 3 and 6 months. CONCLUSION: Hypolipidemic effect of probucol depended on the individual features of lipoproteins metabolic disorders rather than the drug blood concentration. Larger probucol doses fail to reduce cholesterol further.

Adult↗

PubMed2005

Vitamin E supplementation alters HDL-cholesterol concentration and paraoxonase activity in rabbits fed high-cholesterol diet: comparison with probucol.

Vitamin E and probucol are well-known antioxidants that prevent cells from the oxidative stress, which is a risk factor of atherosclerosis. Male rabbits were fed either 0.03% vitamin E or 0.05% probucol in a 0.5% high-cholesterol (HC) diet for 8 weeks. Vitamin E and probucol significantly suppressed an increase in plasma total-cholesterol (total-C) and low-density lipoprotein cholesterol compared to HC-control group. However, plasma high-density lipoprotein-cholesterol (HDL-C) and HDL-C/total-C ratio levels and plasma paraoxonase activity were only significantly higher in vitamin E group after 8 weeks. Hepatic ACAT activity was significantly lower in both vitamin E and probucol groups than in HC-control group, while HMG-CoA reductase activity was the highest only in the probucol group. Total fecal sterol content was significantly higher in probucol and vitamin E groups than in the two control groups. Some atherogenic signs were discovered in the aortic fatty streak of HC-control group, yet not in other groups. Hepatic mRNA expressions of apo B-100 and apo C-III were significantly lower in probucol group than in other groups. Vitamin E supplementation was found to alter the plasma HDL-C-related factors; meanwhile, probucol supplementation was very effective in enhancing cholesterol metabolism, except for a negative effect that reduced plasma HDL-C concentration.

Alanine Transaminase↗

PubMed1993

Positive correlation between probucol in low density lipoprotein and LDL-lowering.

The relationship between the content of probucol in plasma and lipid lowering was studied after administration of probucol. The study group consisted of 44 patients with Type II hyperlipidaemia (mean age 56 y). Total cholesterol level was decreased from 293 to 232 mg.dl-1 by the administration of probucol. The plasma probucol concentration was 2.03 mg.dl-1 after 4 weeks of administration of 500 mg b.d. Although there was no relationship between the change in total cholesterol and the plasma probucol, a linear relation was observed between the decrease in LDL-cholesterol concentration and the probucol concentration in LDL. Neither the VLDL nor the HDL-probucol content were related to the magnitude of the decrease in lipoprotein cholesterol. The present study has demonstrated that an increase in the probucol content in LDL was associated with a decrease in plasma LDL-cholesterol.

Adult↗

PubMed1993

The role of lipids and antioxidative factors for development of atherosclerosis. The Probucol Quantitative Regression Swedish Trial (PQRST).

The effect of probucol on the development of atherosclerosis is being investigated in the Probucol Quantitative Regression Swedish Trial (PQRST). Hypercholesterolemic patients are randomized to receive either probucol 0.5 g twice daily or placebo in a double-blind manner, in combination with dietary therapy and cholestyramine 8-16 g daily for a 3-year period. The primary endpoint of the trial is the change in atheroma volume, assessed by annual quantitative angiography involving 20-cm segments of the femoral artery. Data from the open diet and prerandomization phase indicate that probucol added to dietary intervention plus cholestyramine produced highly significant reductions in total (-17%), low-density lipoprotein (LDL; -10%), and high-density lipoprotein (-30%) cholesterol. From a subpopulation, LDL levels were isolated during different stages of the prerandomization phase. LDL was exposed to the oxidant Cu2+ and binding to fibroblasts as well as degradation by macrophages was measured. The generation of thiobarbituric acid-reactive substances (TBARS) was also measured. Probucol prevented degradation of copper-exposed LDL by macrophages and also reduced the formation of TBARS, indicating that probucol protected LDL from oxidation. After the trial concludes in December 1992, statistical models will be used to investigate how much of the change in atherosclerosis is explained by changes in lipoprotein concentrations and how much is explained by probucol's antioxidative effects. Thus, other metabolic factors such as dietary intake and circulating levels of lipid soluble vitamins and fatty acids that may modify the possible antioxidative effects of probucol are also measured and will be related to change in atherosclerosis.

Aged↗

PubMed1992

Antioxidant activities of probucol against lipid peroxidations.

The antioxidant activities of probucol were measured in the oxidations of methyl linoleate in homogeneous solution and soybean phosphatidylcholine liposomal membranes and also of low-density lipoproteins. When an excess amount of probucol was reacted with galvinoxyl, the EPR spectrum of galvinoxyl disappeared and a new triplet EPR signal was found: g = 2.0058 and aH(2H) = 0.14 mT. The identical EPR spectrum was observed when probucol was reacted with tert-butoxyl radical generated from di-tert-butylperoxy oxalate. This EPR signal disappeared rapidly when reacted with either alpha-tocopherol or 6-O-palmitoyl-ascorbic acid. Probucol suppressed the free-radical-mediated oxidations of methyl linoleate in hexane and in acetonitrile, in a dose-dependent manner. Its antioxidant activity was 17.5-fold less than that of alpha-tocopherol in hexane. Probucol incorporated into soybean phosphatidylcholine liposomes suppressed its oxidation. The antioxidant activity of probucol was less than that of alpha-tocopherol, but the difference between the two antioxidant activities was smaller in the membranes than in homogeneous solution. Probucol also suppressed the oxidation of low-density lipoprotein. Interestingly, probucol suppressed the oxidation of LDL as efficiently as alpha-tocopherol, implying that physical factors as well as chemical reactivity are important in determining the overall activity of antioxidant in low-density lipoprotein.

Antioxidants↗

PubMed1994

Measurement of plasma probucol levels by high-performance liquid chromatography.

An improved assay for measuring plasma levels of probucol using reversed-phase high-performance liquid chromatography has been developed and used to measure probucol in cholesterol-fed rabbits. The sample was extracted with iso-octane, reconstituted in acetonitrile and was analysed using a Hypersil ODS column with a mobile phase consisting of acetonitrile-water (96:4, v/v). Detection was carried out using ultraviolet absorption at 241 nm. The lower detection limit for plasma probucol was 0.5 micrograms/ml. Inter-assay and intra-assay coefficients of variation were 1.8-4.8% and 1.6-3.3%, respectively. The method was applied to measurements of probucol in plasma from rabbits receiving a diet containing 1% probucol and 2% cholesterol for five weeks. Probucol levels at five weeks were significantly higher in the animals receiving concomitant cholesterol, and were close to the steady-state values predicted from the one week measurements. Also, the plasma probucol levels were positively correlated with total plasma cholesterol (r = 0.87, p < 0.001). The results indicate that bioavailability of probucol is dependent on the lipid content of the diet.

Animals↗

PubMedDate not supplied

Atherosclerotic lesion development in hypercholesterolemic Japanese quail following probucol treatment: a biochemical and morphologic evaluation.

Probucol, a cholesterol-lowering agent which possesses antioxidant properties, was evaluated in hypercholesterolemic Japanese quail in order to assess the significance of antioxidant therapy on the development of atherosclerosis. Forty quail were fed a 0.5% cholesterol diet containing 0, 100, 200 or 500 mg kg-1 probucol for 2 months. At necropsy, plasma total and lipoprotein cholesterol and lipoprotein distribution were unchanged despite plasma probucol levels of 50 to 59 micrograms ml-1. The cholesteryl ester content of the liver and blood vasculature (brachiocephalic artery and aortic arch combined) was reduced by 33% and 62%, respectively, in animals given 500 mg kg-1 probucol. The vascular free cholesterol content was also reduced by 43 to 60% over the probucol dose range. Morphometric analysis of the brachiocephalic artery revealed that probucol reduced the incidence of lesions containing esterase-positive cells from 62% in untreated animals to 26% and 13% in animals administered 200 and 500 mg kg-1 probucol, respectively. No difference in mean wall thickness or area of the bracheocephalic artery was noted between the groups. Thus, we conclude that probucol can blunt the cholesteryl ester and macrophage enrichment of atherosclerotic lesions and this activity appears to be mediated by the compound's antioxidant properties since the changes noted were seen in the absence of alterations in plasma total and lipoprotein cholesterol levels.

Animals↗

PubMed2003

Modulation of HDL metabolism by probucol in complete cholesteryl ester transfer protein deficiency.

Probucol, an antioxidative and hypolipidemic agent, has been postulated to increase reverse cholesterol transport by enhancing cholesteryl ester transfer protein (CETP) activity. However, its clinical implication in CETP deficient patients has not been fully defined. To characterize the effects of probucol in the absence of CETP, we evaluated the changes in lipid profile, lipid peroxidation, and paraoxonase 1 (PON1) activity in two complete CETP deficient patients, caused by treatment with probucol. When the patients were not receiving probucol, low-density lipoprotein (LDL) particles were smaller and high-density lipoprotein (HDL) particles were larger in these patients than in controls. Treatment with probucol (500 mg/day) resulted in the decrease in the levels of HDL-C and apolipoprotein (apo) A-I up to 22%. The size of HDL particles became smaller. LDL cholesterol concentration did not change in one patient, while it decreased by 47% in the other. PON1 activity/HDL-C, which was about 40% lower in the patients before treatment than in controls with the matching PON1 genotype, increased by 30% during the treatment. Lag time for LDL and HDL in both cases became prolonged more than 1.8 times after administration of probucol. This study demonstrated for the first time that probucol reduces HDL-C even in humans with complete CETP deficiency. Probucol treatment in these patients was also associated with protection of lipoproteins against oxidative stress, suggesting a clinical benefit of this drug even in such a state.

Aged↗