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PubMed1999

Lysophosphatidylcholine molecular species in low density lipoprotein and high density lipoprotein in alloxan-induced diabetic rats: effect of probucol.

To elucidate the contribution of diabetic state toward the accumulation of lysophosphatidylcholine (LPC) in low density lipoprotein (LDL), the LPC molecular species in LDL and high density lipoprotein (HDL) obtained from alloxan-induced diabetic rats were determined by high performance liquid chromatography. The palmitoyl LPC (PLPC) per protein was increased in the LDL of diabetic rats (p < 0.05), whereas the stearoyl LPC (SLPC) decreased in both the LDL and HDL of diabetic rats (p < 0.001) in comparison to nondiabetic rats. After the dietary administration of probucol for 4 weeks, the concentrations of SLPC and PLPC in the LDL of diabetic rats and of SLPC in the LDL of nondiabetic rats all significantly decreased by probucol (all; p < 0.01), with a concomitant decrease of the plasma concentrations of total and HDL cholesterol, and phospholipid, compared with those without probucol. The level of TBARS per protein in LDL increased in diabetic rats, and decreased by probucol (p < 0.01). In conclusion, the oxidative stress is thought to be an important factor to accumulate LPC in LDL, although the paradoxical decrease of SLPC in diabetic LDL suggests a non-oxidative metabolism with a preference for the LPC molecular species. The reducing effect of probucol on LPC may not be solely attributed to its antioxidative effect.

Animals↗
PubMed1992

Effects of probucol on plasma lipids, lipoproteins and parameters of high density lipoprotein metabolism.

Eight patients with primary hypercholesterolemia were treated with probucol for 17 weeks. Plasma total cholesterol, low density lipoprotein (LDL)-cholesterol, and high density lipoprotein (HDL)-cholesterol decreased by 16.6, 15.0 and 25.7%, respectively, in response to probucol treatment. Plasma levels of apolipoprotein B and apolipoprotein A-I also decreased, while apolipoprotein A-II concentrations were unchanged. The decrease in HDL-cholesterol levels was associated with a reduction in HDL particle size. No changes in the plasma lecithin:cholesterol acyltransferase activity or mass occurred in response to probucol treatment. In contrast, a significant 25% increase in plasma cholesteryl ester and triglyceride transfer activity occurred following probucol treatment. There was a positive correlation (R = 0.94) between cholesterol ester and triglyceride transfer. We propose that the increase in lipid transfer activity may in part explain the changes in HDL concentration and size, as well as the previously reported effect probucol has on reducing atherosclerosis in animal models.

Aged↗
PubMed1987

Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.

It has been postulated that low density lipoprotein (LDL) becomes fully atherogenic only if it first undergoes oxidative modification. The oxidatively modified form, but not native LDL, is recognized by the acetyl-LDL or "scavenger" receptor and could, therefore, be taken up rapidly by tissue macrophages to generate the fatty-streak lesion of atherosclerosis. However, there is thus far very little direct evidence for oxidative modification in vivo. The studies reported here take advantage of the fact that probucol is an effective antioxidant transported in lipoproteins, including LDL, and blocks the oxidative modification of LDL in vitro. We now show that the rate of degradation of LDL in the macrophage-rich fatty-streak lesions of the LDL receptor-deficient rabbit treated with probucol (1% by weight in the diet) is reduced to about one-half of that in the lesions of receptor-deficient rabbits not given probucol (but matched for plasma cholesterol levels). In contrast, the rates of degradation in the nonlesioned areas of the aorta were no different in probucol-treated and control animals. Most of the LDL degradation in fatty-streak lesions takes place in macrophages, whereas in nonlesioned aorta, which contains very few macrophages, the degradation is almost exclusively in endothelial cells and smooth muscle cells. Thus, the results are compatible with the postulate that the native LDL taken up and degraded by foam cells in the developing fatty-streak lesions was in part first converted to a form recognized by the scavenger receptor (by oxidative or analogous modification). Finally, and most importantly, we show that treatment with probucol significantly reduced the rate of development of fatty-streak lesions even though plasma cholesterol levels were no lower than lovastatin-treated (control) rabbits.

Animals↗
PubMed1995

Inhibitory effect of probucol on nephrotoxicity induced by ferric nitrilotriacetate (Fe-NTA) in rats.

Effects of dietary probucol on renal damage induced by a renal carcinogen, ferric nitrilotriacetate (Fe-NTA), in male Wistar rats were quantitatively investigated with a computer-mediated image analyzer. The kidneys of rats fed a 1% probucol diet were protected from necrosis and lipid peroxidation induced by a single i.p. treatment with Fe-NTA solution at 5 mg Fe/kg body wt and were significantly resistant to a higher dose. For the parameter of lipid peroxidation, Schiff's staining method was utilized to demonstrate the extent of formation of aldehydes, products of lipid peroxidation. Thus following injection of Fe-NTA solution at 10 mg Fe/kg body wt the average areas of tubular necrosis were 85.8% versus 56.9% and the positive areas for Schiff's staining were 15.3% versus 5.6% in the renal cortices of rats fed control of 1% probucol diets respectively. These results indicate that probucol provides protection against Fe-NTA-induced nephrotoxicity through its antioxidant properties. In addition to being a cholesterol-lowering drug, useful for the control of hypercholesterolemia, probucol may therefore be beneficial for prevention and treatment of various pathogenic processes including those leading to carcinogenesis.

Animals↗
PubMed1995

Inhibitory effect of probucol on benzo[a]pyrene induced lung tumorigenesis.

The effects of probucol, a clinically used cholesterol lowering and antioxidant drug, on benzo[a]pyrene (B[a]P) induced pulmonary and forestomach tumorigenesis as well as induction of colonic aberrant crypt foci (ACF) in female A/J mice was investigated. Diet containing 1% probucol fed prior to, during and after 8 bi-weekly 1 mg/mouse oral intubations of B[a]P, reduced the number of pulmonary adenomas by 52% (P < 0.001) and the number of forestomach tumors by 31%. The 0.06% probucol diet also resulted in decreased tumor formation but the differences did not reach statistical significance. Both probucol diets significantly reduced the numbers of large ACF, putative preneoplastic lesions of the colon mucosa, but showed no effects on the total numbers of ACF. The results of this study suggest that probucol may also be useful as a chemopreventive agent, in addition to being a cholesterol lowering and anti-atherogenic drug with low toxicity.

Animals↗
PubMed2006

Role of probucol on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy.

The lipid-lowering agent probucol may be efficacious, through its antioxidant properties, to limit and reverse the vascular endothelial dysfunction associated with left ventricular hypertrophy (LVH). LVH was induced by performing an aortic banding (AB) on swine, except for controls (group 1). The untreated AB group received a placebo (group 2) whereas the treated groups received probucol (1000 mg/d orally); the third group began its treatment on the day of the banding (for 60 d), the fourth began on day 30 and the fifth on day 60 after AB (both for 30 d). Hypertrophy was assessed by echocardiography and histology. Coronary vascular reactivity was evaluated in organ chambers and endothelial function by quantification of NO2/NO3 and cyclic guanosine-3',5'-monophosphate. To assess oxidative stress, hydroperoxides and angiotensin II levels as well as superoxide dismutase activity were evaluated. After treatment with probucol, a significant decrease in left ventricle/body weight ratio was observed compared with the untreated group. Dose-response curves of the probucol groups showed an improvement in endothelium-dependent relaxations, associated with increased nitric oxide bioavailability and decreased angiotensin II and hydroperoxide levels. In conclusion, the antioxidant probucol limited the development and induced the regression of LVH and the associated coronary endothelial dysfunction.

Angiotensin II↗
PubMed1999

An antioxidant, probucol, induces anti-angiogenesis and apoptosis in athymic nude mouse xenografted human head and neck squamous carcinoma cells.

Probucol is a very strong synthetic antioxidant that was been safely used for the treatment of hyperlipidemia in Japan since 1985. It has been reported that lipid oxidation products can alter growth factor production, which could influence smooth muscle cell proliferation. Oxidized low density lipoprotein can influence smooth muscle cell proliferation by enhancing the expression of platelet-derived growth factor (PDGF)-AA gene and PDGF receptor in vascular smooth muscle cell. Further, free radical reactions can cause irreversible alterations of genomic constituents during the initiation phase of carcinogenesis. Antioxidant is considered to protect lipids and low density lipoprotein (LDL) from oxidation, which potentially inhibits angiogenesis, and rapid removal of free radicals by antioxidants could have an anti-carcinogenic effect. In the present study, we investigated whether antioxidant treatment with probucol had an antitumor effect on KB cells, a human head and neck squamous carcinoma cell line. Probucol did not have any effect on KB cells in vitro, but probucol treatment of KB cells xenografts in mice had a significant antitumor effect through anti-angiogenic and apoptosis-inducing actions. These results support the idea that probucol is useful for preventing and/or treating cancer.

Animals↗
PubMed1989

Structural changes in oxidised low-density lipoproteins and of the effect of the anti-atherosclerotic drug probucol observed by synchrotron X-ray and neutron solution scattering.

The atherosclerotic properties of low-density lipoproteins (LDL) are thought to be strongly enhanced by oxidation. The lipid-lowering drug probucol reduces the susceptibility of LDL to oxidation. Synchrotron X-ray and high-flux neutron solution scattering curves were used to characterise the structural properties of human LDL, before and after modification by oxidation with Cu2+ and the addition of probucol, in order to evaluate these techniques. Analyses based on Guinier plots, simple two-shell spherical modelling, and the use of cubic splines and indirect transformation show that a 20-h incubation with Cu2+ ions (but not 6 h) causes some of the LDL to associate to form larger aggregated particles. Gel electrophoresis on Cu2+ -oxidised LDL shows a concomitant degradation of the apolipoprotein B-100 as well as the formation of high molecular mass forms. These experiments indicate that the apoprotein B-100 structure has been significantly disrupted by oxidation. The addition of probucol to LDL causes an increase in the polydispersity of LDL, as evidenced by small changes in the Guinier curves and some weakening of the minima in the X-ray scattering curves. No changes in the quasispherical shape of LDL are observed and gel electrophoresis indicates no changes. It is possible that probucol may exert its effect by increasing the range of sizes of LDL and that the lipid-lowering effect of probucol in vivo might be caused by the preferential catabolism of the higher molecular mass forms of LDL thus created.

Apolipoprotein B-100↗
PubMed2006

Effects of alpha tocopherol and probucol supplements on allergen-induced airway inflammation and hyperresponsiveness in a mouse model of allergic asthma.

OBJECTIVE: We investigated the role of antioxidants in airway hyperresponsiveness to acetylcholine using young asthma model mice, which were sensitized and stimulated with ovalbumin. METHODS: The mice had been fed either a normal diet, an alpha-tocopherol-supplemented diet or a probucol-supplemented diet 14 days before the first sensitization. They were immunized with antigen at intervals of 12 days and, starting from 10 days after the second immunization, they were exposed to antigen 3 times every 4th day using an ultrasonic nebulizer. Twenty-four hours after the last antigen inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was collected. A blood and lung tissue study was also carried out. RESULTS: Twenty-four hours after the last antigen challenge, both IL-4 and IL-5 in the BALF of alpha-tocopherol-supplemented mice were significantly decreased. The IL-5 level in probucol-supplemented mice was also decreased, but there was no difference in IL-4 levels. The serum IgE level was decreased in probucol-supplemented mice. Differential cell rates of the fluid revealed a significant decrease in eosinophils due to antioxidant supplementation. Airway hyperresponsiveness to acetylcholine was also repressed in antioxidant-supplemented mice. In histological sections of lung tissue, inflammatory cells and mucus secretion were markedly reduced in antioxidant-supplemented mice. We investigated the antioxidant effect on our model mice by examining 8-isoprostane in BALF and lung tissue, and acrolein in BALF; however, our experiment gave us no evidence of the antioxidant properties of either alpha-tocopherol or probucol contributing to the reduction of airway inflammation. CONCLUSION: These findings indicate that alpha-tocopherol and probucol suppress allergic responses in asthma model mice, although these two drugs cause suppression in different ways that are unrelated to antioxidation.

Acrolein↗
PubMedDate not supplied

Efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin in hyperlipidemic patients treated with probucol.

The objective of this open trial was to investigate the efficacy and safety of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor fluvastatin in hypercholesterolemic patients already receiving probucol. All of the participants had hypercholesterolemia. i.e. serum total cholesterol > or = 220 mg/dl, despite administration of probucol, 500 mg/day, for more than 4 weeks. After this, fluvastatin, 30 mg/day, was added to probucol treatment for 12 weeks. Twenty-seven patients were recruited into this study; all were evaluated for safety, and 22 were evaluated for efficacy. The addition of fluvastatin to the probucol regimen produced a significant further reduction in serum total and low-density lipoprotein cholesterol concentrations (of 18 and 20%, respectively; p < 0.001); these effects were fully established within 4 weeks of treatment and were maintained throughout the treatment. Fluvastatin did not affect the serum high-density lipoprotein cholesterol concentration. Fluvastatin treatment decreased serum triglyceride concentrations slightly in all patients (not significant); in patients with hypertriglyceridemia, triglyceride levels were decreased significantly by 34% (p < 0.01; serum triglycerides > or = 150 mg/dl). In addition, fluvastatin significantly decreased serum apolipoprotein B, C-II, C-III and E levels, whereas serum apolipoprotein A-I and A-II levels were unaffected. One patient complained of slight abdominal discomfort during fluvastatin administration, but relationship to fluvastatin remains unclear. One patient had slight elevation of the serum alanine aminotransferase level, and another patient had an elevated gamma-glutamyl transferase level. The addition of fluvastatin to probucol treatment can be considered to be an effective and well tolerated treatment in hypercholesterolemic patients.

Adult↗
PubMedDate not supplied

Increase in plasma cholesteryl ester transfer protein during probucol treatment. Relation to changes in high density lipoprotein composition.

Probucol is a hypolipidemic agent that causes a marked decrease in high density lipoprotein (HDL) cholesterol. To investigate the mechanism of this effect, two studies were performed in hypercholesterolemic patients who had been stabilized previously on diet and were not receiving other lipid-lowering medication. Plasma cholesteryl ester transfer protein (CETP) concentrations were measured in fasting plasma samples before and after 10 weeks of probucol therapy using a sensitive and specific radioimmunoassay. Plasma total and low density lipoprotein cholesterol concentrations decreased, whereas apolipoprotein (apo) B was unchanged. Plasma apo E concentrations increased markedly. HDL cholesterol and apo A-I decreased in all subjects. These effects of probucol were accompanied by even more striking changes in plasma CETP concentrations, which increased by a mean of 64%. In a second study of six hypercholesterolemic subjects, the time-course effects of probucol on CETP and HDL subspecies were studied. Significant increases in plasma apo E and in CETP occurred after 4 weeks, and CETP, but not apo E, increased further after 16 weeks of treatment. Concomitant and opposite changes occurred in HDL composition, with decreases in HDL cholesterol and lipoprotein containing apo A-I. The increase in plasma CETP concentrations, the decrease in HDL cholesterol, and the increase in plasma apo E concentrations observed during probucol treatment are changes consistent with a postulated increase in reverse cholesterol transport via the remnant pathway.

Apolipoprotein A-I↗
PubMedDate not supplied

Probucol decreases apolipoprotein A-I transport rate and increases high density lipoprotein cholesteryl ester fractional catabolic rate in control and human apolipoprotein A-I transgenic mice.

Probucol effects on lipoprotein metabolism were determined in control and human apolipoprotein A-I transgenic (HuAITg) mice. In control mice, probucol reduced total cholesterol from 67 +/- 2 to 25 +/- 2 mg/dl by reducing high density lipoprotein (HDL) cholesterol from 46 +/- 20 to 14 +/- 1 mg/dl and low density lipoprotein (LDL) cholesterol from 11 +/- 1 to 5 +/- 1 mg/dl. Apolipoprotein (apo) A-I levels were reduced from 122 +/- 8 to 56 +/- 5 mg/dl. In HuAITg mice, probucol reduced total cholesterol from 121 +/- 5 to 77 +/- 3 mg/dl by reducing HDL cholesterol from 84 +/- 4 to 56 +/- 3 mg/dl and LDL cholesterol from 19 +/- 2 to 11 +/- 2 mg/dl. Human apo A-I levels were reduced from 267 +/- 13 to 144 +/- 12 mg/dl and mouse apo A-I levels from 18 +/- 2 to 9 +/- 2 mg/dl. Control animals have primarily a monodisperse HDL with a particle diameter of 10 nm. Probucol did not appear to change the particle size distribution in the control animals. The HuAITg mice have a polydisperse HDL with particle diameters of 10.1 and 8.5 nm. Probucol treatment of these animals resulted in HDL with particle diameters of 9.4 and 8.5 nm, apparently reducing the size of the larger particles. In vivo turnover studies revealed that the reduction in apo A-I was primarily due to a decrease in transport rate, whereas the reduction in HDL cholesterol was primarily due to an increase in HDL cholesteryl ester fractional catabolic rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of probucol dosage on plasma lipid and lipoprotein levels and on protection of low density lipoprotein against in vitro oxidation in humans.

To determine whether probucol's ability to confer antioxidant protection to low density lipoprotein (LDL) could be dissociated from its ability to lower high density lipoprotein (HDL) cholesterol, 17 hypercholesterolemic patients were treated with either a standard dose, 1 g/day (4 tablets), or a low dose, 250 mg/day (1 tablet), of probucol for a 6-month period. Effects of therapy on lipoprotein levels and on susceptibility of LDL to in vitro oxidation were measured at frequent intervals. Probucol levels in plasma LDL rose less rapidly in the 1-tablet group but were nearly 50% of levels in the 4-tablet group after 6 months. HDL cholesterol and apolipoprotein A-1 decreased 17.6% and 27.9%, respectively, in the 1-tablet group compared with 28.0% and 38.3%, respectively, in the 4-tablet group (p = 0.07 and p = 0.06). In the 4-tablet group, LDL was protected from copper and endothelial cell-mediated oxidation after 2 months of therapy. In the 1-tablet group, equal degrees of protection occurred, but only after 6 months of therapy. In the whole study group, the decrease in LDL susceptibility to copper or endothelial cell-mediated oxidative modification was correlated with the content of probucol in LDL (r = 0.73, r = 0.65, p less than 0.005). Additionally, the decrease in HDL cholesterol level was correlated with the increase in protection to LDL from oxidative modification (r = 0.67 for copper, r = 0.58 for endothelial cells, p less than 0.05 for both) and also with the content of probucol in LDL (r = 0.6, p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol, HDL↗
PubMed2002

Beneficial effects of long-term use of the antioxidant probucol in heart failure in the rat.

BACKGROUND: Congestive heart failure (CHF) is a disease that is characterized by progressive left ventricular (LV) dysfunction and dilatation. Oxidative stress is thought to contribute to the progression of CHF, and antioxidants have been shown to have beneficial effects when started early after myocardial infarction (MI). In this study, we tested whether the powerful antioxidant probucol would attenuate progression of CHF once it was established after MI in the rat. METHODS AND RESULTS: Ligation of a coronary artery was used to create an MI in rats (n=266). Survivors were then randomized 20 days after MI to either probucol 61 mg. kg(-1). d(-1) or vehicle and followed up for a total of 100 days after MI. Studies of cardiac hemodynamics, LV remodeling, cardiac apoptosis and morphology, systemic neurohumoral activation, oxidative stress, and renal function were then evaluated. Probucol improved LV function (LV maximum rate of pressure rise from 3103 to 4250 mm Hg/s, P<0.05, and LV end-diastolic pressure decrease from 28 to 24 mm Hg, P<0.05), reduced pulmonary weights, prevented right ventricular systolic hypertension, and preserved renal function compared with vehicle. Probucol also prevented LV dilatation, prevented wall thinning (1.70 versus 1.42 mm, P<0.05), reduced cardiac fibrosis and cardiac apoptosis, attenuated increased myocardial cell cross-sectional area, and increased scar thickness. CONCLUSIONS: In chronic CHF, probucol exerts multiple beneficial morphological effects that result in better LV remodeling and function, reduced neurohumoral activation, and preserved renal function.

Animals↗
PubMed2000

Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol.

BACKGROUND: The clinical usefulness of adriamycin is restricted by the development of congestive heart failure. It has been suggested that probucol, a strong antioxidant, completely prevents adriamycin-induced cardiomyopathy without interfering with its antitumor properties. The present study investigated the effects of adriamycin and probucol on myocardial antioxidant enzyme activities and immunoreactive protein levels in rats. METHODS AND RESULTS: Activities and protein levels of glutathione peroxidase (GSHPx) were significantly decreased from 2 to 24 hours, and those of manganese superoxide dismutase were decreased at 1 and 2 hours after adriamycin treatment. These changes were prevented by probucol. Catalase activity was increased from 2 to 24 hours after adriamycin treatment, but its protein levels were not significantly changed. Copper zinc superoxide dismutase activity and protein level were not changed at any time. Myocardial lipid peroxidation was found to be significantly higher at all time points, and this change was also prevented by probucol. Treatment with probucol alone increased GSHPx activity at 2 weeks, and in these hearts, lipid peroxidation was lower than the control value. Within 24 hours, there was no mortality in any of the groups. CONCLUSIONS: It is suggested that an early and persistent decrease in GSHPx activity and protein may play an important role in the pathogenesis of adriamycin-induced cardiomyopathy, worsening heart failure and mortality.

Animals↗
PubMed1991

Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification.

Several lines of evidence indicate that the oxidative modification of low density lipoproteins (LDL) may provide an important link between plasma LDL and the genesis of the atherosclerotic lesion. Ascorbate is an important water-soluble, chain-breaking antioxidant in humans. Probucol, a lipid-soluble antioxidant drug has been shown to retard the progression of atherosclerosis. The aim of the present study was to compare the effects of probucol and physiologic levels of ascorbate on the oxidative modification of LDL in both a cell-free (2.5 microM Cu++ in phosphate-buffered saline) and cellular system (human monocyte macrophages in Ham's F-10 medium). Both ascorbate and probucol inhibited the oxidative modification of LDL in both systems to a similar degree as evidenced by the thiobarbituric acid-reacting substance activity, electrophoretic mobility, and degradation by macrophages. However, whereas co-incubation with physiologic levels of ascorbate resulted in a substantial preservation of the alpha-tocopherol, gamma-tocopherol, and beta-carotene of the LDL, probucol in concentrations ranging from 10 to 80 microM failed to protect these antioxidants. Thus, in addition to being as potent as probucol in inhibiting the oxidation of LDL, ascorbate in contrast preserves the endogenous antioxidants in the LDL.

Ascorbic Acid↗
PubMedDate not supplied

The effect of probucol on oxidized cholesterol disposition in hyperlipidaemic patients.

Probucol is a cholesterol-lowering and antioxidant drug that has been shown to inhibit or delay the progression of atherosclerosis. This antiatherosclerotic effect may result from the removal of oxidized cholesterol on the surface of low-density lipoprotein (LDL). To investigate whether probucol transfers oxidized cholesterol from LDL to urine, urine samples were obtained from five patients with hypercholesterolaemia treated with 500-mg probucol orally daily and from five healthy controls. Using gas chromatography-mass spectrometry, we identified cholesteryl-6-(2,6-di-tertiary butylphenol-4)-thioether (CT) in the urine samples from patients with hypercholesterolaemia but not from healthy controls. This result suggests that probucol is hydrolysed to form 4-mercapto-2,6-di-tertiary butylphenol (MBP) which conjugates with cholesterol-5 alpha, 6 alpha-epoxide, oxidized cholesterol, resulting in the formation of CT in vivo. In addition to its hypolipidaemic and antioxidant actions, probucol may act to prevent atherosclerosis by increasing the urinary excretion of oxidized cholesterol.

Anticholesteremic Agents↗
PubMed2003

Probucol decreases mevalonate pyrophosphate decarboxylase in the rat liver.

It is known that cholesterol biosynthesis in the liver is inhibited by probucol. This inhibition by probucol is caused at least in part by a decrease in 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity. In this study, we examined serum cholesterol and the change in the activity or protein level of mevalonate pyrophosphate decarboxylase (MPD), which is involved in cholesterol biosynthesis, in the livers of rats fed probucol. The results indicated that serum cholesterol, MPD activity and MPD protein were decreased by 70, 50 and 60% by probucol, respectively, as compared with those in rats fed normal chow. These data show for the first time that probucol decreases the level of an enzyme involved in cholesterol biosynthesis other than HMG-CoA reductase.

Animals↗