© 1995 American Heart Association, Inc.
Articles |
Probucol Treatment Decreases Serum Concentrations of Diet-Derived Antioxidants
From the Department of Internal Medicine, King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden (L.S.E., J.J., G.W.); the Dietetics Department, Karolinska Hospital, Stockholm, Sweden (K.H.); the Research Center of General Medicine, North West Health Board, Stockholm County Council, Sweden (J.J.); the Department of Internal Medicine, University Hospital, Linköping, Sweden (J.M., A.G.O.); and The Life Insurance Companies Institute for Medical Statistics, Ullevål Hospital, Oslo, Norway (I.H.).
Correspondence to Liselotte Schäfer Elinder, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden.
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Abstract |
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Abstract The effect of probucol, which is both a cholesterol-lowering drug and an antioxidant, on the serum concentrations of diet-derived antioxidants vitamin E, ß-carotene, lycopene, and vitamin A was studied in 303 hypercholesterolemic subjects. In a 3-year, double-blind, randomized trial we investigated to determine whether combined treatment with diet, cholestyramine, and probucol could reduce the progression of femoral atherosclerosis. Serum and lipoprotein antioxidant levels were measured by reverse-phase high-performance liquid chromatography. Cholestyramine significantly lowered serum concentrations of vitamin E by 7%, ß-carotene by 40%, and lycopene by 30% (all P<.001) due to impairment of gastrointestinal absorption and to serum cholesterol lowering. Probucol reduced serum vitamin E by 14% (P<.001) secondary to cholesterol and triglyceride lowering. The carotenoids were reduced by probucol by 30% to 40% (P<.001) most probably due to reductions in lipoprotein particle size and to competition with these substances for incorporation into VLDL during its assembly in the liver. This study shows that the use of a lipid-soluble antioxidant and cholesterol-lowering drug may have unfavorable effects on blood levels of diet-derived antioxidants.
Key Words: hypercholesterolemia • cholestyramine • probucol • vitamin E • ß-carotene
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Introduction |
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Reduction of blood lipid levels and use of antioxidant therapy are currently two major approaches to reduce the incidence of cardiovascular diseases. Probucol combines both strategies in one drug, which has created great expectations on its effect in humans. LDL from probucol-treated patients has been shown to be resistant to oxidative modification.1 2 3 In studies with the Watanabe heritable hyperlipidemic rabbit, probucol has been shown to inhibit atherosclerosis development.4 However, the first double-blind clinical trial in humans, from which the data in the present report are derived, showed no protective effect of probucol on femoral atherosclerosis development over a 3-year period in hypercholesterolemic subjects.5 One potential problem with probucol use in humans is that it lowers HDL,5 6 which is known to protect against cardiovascular disease.7
According to the oxidation hypothesis of atherosclerosis
development,8 oxidative modification of LDL occurs in the
arterial wall of subjects with atherosclerosis. Therefore we
investigated the effect of the lipid-soluble antioxidant drug probucol
on the serum and lipoprotein concentrations of the diet-derived and
lipid-soluble antioxidants vitamin E (
-tocopherol), lycopene, -
and ß-carotene, and vitamin A, which has not previously been studied
in-depth. Because probucol lowers serum cholesterol and cholesterol is
a positive predictor of lipid-soluble antioxidants,9
direct as well as indirect actions of probucol on diet-derived
antioxidants are possible. Whereas vitamin A is bound to
retinol-binding protein in serum in a 1:1
complex,10 vitamin E, the carotenes, lycopene, and
probucol are distributed to more than 95% in serum
lipoproteins,11 12 13 where interactions among these
substances could take place.
The present report shows that probucol lowers the serum concentration of all diet-derived antioxidants by mechanisms unrelated to its antioxidant properties.
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Methods |
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Study Population and Treatment
The Probucol Quantitative Regression Swedish Trial (PQRST) population consisted of 303 hypercholesterolemic patients under 71 years of age. All patients received dietary advice and cholestyramine as a basic treatment and either probucol or placebo. The design of the study, patient characteristics, and inclusion and exclusion criteria have been previously reported.5 A 6-month prerandomization phase was followed by a 3-year double-blind phase. Dietary habits were assessed by a combined method using menu registration and a dietary history interview.9 Dietary advice was given according to the American Heart Association Step 1 diet (total fat <30% of total calories, saturated fat <10% of total calories, and cholesterol <300 mg/d).14 Dietary habits were monitored repeatedly throughout the trial. After testing the effect of diet changes on serum lipids for 2 months in the prerandomization phase, cholestyramine was added for 2 months, followed by probucol for another 2 months. All patients randomized to probucol or placebo had visually detectable atherosclerosis on their femoral angiograms. Thirty-eight percent of all participants had clinical symptoms of cardiovascular disease. The dose of cholestyramine recommended to each patient varied according to tolerance, from 8 to 16 g/d. The mean dose of cholestyramine taken by the probucol and the placebo groups was not significantly different. The dosage of probucol or placebo was 0.5 g BID. Compliance with both drug regimens was estimated by patient interview and by pill count. Patients remained on their usual medication throughout the trial. The average consumption of other drugs did not differ between the groups.
The study was approved by the ethics committee at the Karolinska Institute in Stockholm, Sweden.
Laboratory Analysis
Serum samples were collected from all participants eight times
during the 3-year trial and frozen at -70°C. The number of samples
analyzed each time varied from 262 to 303 because of lack of
sample material or technical reasons. All samples from one person were
analyzed on the same day. In 84% of the patients all eight
samples were available. Vitamin A (retinol), vitamin E
(-tocopherol), - and ß-carotene, lycopene, and
probucol were analyzed simultaneously by
reverse-phase high-performance liquid
chromatography as described previously.15
A serum pool was stored at -70°C and analyzed daily. This
gave the following coefficients of variation during a 2-year period:
probucol 4.2%, -tocopherol 7.2%, lycopene 12.3%,
-carotene 11.3%, ß-carotene 9.7%, and retinol 4.8%. The levels
of all substances in the serum pool were stable. This was also true for
a serum pool devoid of probucol.
LDL and VLDL were isolated from fasting fresh EDTA-plasma by ultracentrifugation in an NaCl gradient.16 HDL was isolated from EDTA-plasma by sequential ultracentrifugation in NaBr gradients.17 Cholesterol and triglycerides were determined by nonenzymatic methods,18 19 and protein was measured by Lowry's method, with bovine serum albumin as the protein standard.20
Antioxidants were analyzed in lipoprotein fractions in 15 consecutive patients who had been in the trial for about 2 years at the time of sampling. By chance the distribution of these patients between the probucol (n=10) and the placebo groups (n=5) was uneven. Antioxidants were extracted from 1-mL samples of nondialyzed lipoproteins in the same way as from serum samples.
HDL particle size was determined by gradient gel electrophoresis21 in a representative subset of the patients. The particles quantified were in decreasing size HDL2b, HDL2a, HDL3a, HDL3b, and HDL3c. LDL particle size was estimated by the ratio of LDL to apoB.22 ApoB was determined by radioimmunoassay according to the instructions given by the manufacturer (Pharmacia Diagnostics).
Statistical Analysis
The distributions of serum antioxidants were skewed, and these
variables were therefore logarithmically transformed before being
used in any statistical tests. The effects of the diet and drugs on
serum antioxidants during the prerandomization phase were tested by
Student's paired t test.
To determine whether probucol and cholestyramine exerted effects on serum concentrations of dietary antioxidants independent of their effects on serum lipids, multiple regression models were set up. Serum antioxidant concentrations were adjusted with regard to lipids using regression coefficients from the initial visit before any treatment was given. The individual means of the last three annual postrandomization measurements of each adjusted serum antioxidant were calculated and entered as the dependent variables in the final models. The average cholestyramine dose and serum probucol concentration of the last three annual measurements were entered as the predictors together with previously established predictors of serum lipid-soluble antioxidants, such as age, body mass index, smoking habits, alcohol consumption, and dietary intake of vitamin E.9
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Results |
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Compliance With Drug Regimens
Compliance with both drug regimens did not differ significantly between the treatment groups. By pill counting, the average dosage of cholestyramine taken was estimated to be 13.1±3.2 g/d (mean±SD) at year 1 and 12.7±3.8 g/d at year 3. The average dosage of probucol was 0.91±0.14 g/d at year 1 and 0.92±0.14 g/d at year 3.
Diet
The intake of major nutrients at the start of the study, before
randomization, and after 3 years in the trial is given in Table 1
. There were no significant differences in intake of
major nutrients between the two treatment groups at any time, and the
data were therefore pooled. Improvements in the dietary quality
resulted in a lowering of fat and total energy intake as well as
increases in the intake of polyunsaturated fatty acids and vitamin E.
After randomization no major changes were made in the composition of
the diet. The intake of major nutrients by the patients during the
trial phase met the American Heart Association Step 1 diet
criteria.
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Lipids
Changes due to treatment in serum total cholesterol
and total triglycerides are given in Fig 1.
The probucol-induced reduction in serum cholesterol was
reversed after 6 months in the placebo group. It took 12 months for
serum triglycerides to return to the pre-probucol
level.
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Probucol
The serum probucol concentration of the patients in the two
treatment groups is shown in Fig 2. At the time of
randomization all patients had received probucol for 2 months, and
after this no further increase in the serum probucol concentration was
seen in the probucol group. Total cholesterol
(r=.19, P<.001) and total
triglycerides (r=.43, P<.001) were
positively associated with the serum probucol concentration. ApoB
concentration correlated positively with probucol (P<.01),
whereas a negative correlation was seen between HDL
cholesterol and probucol (P<.001). After 2
months on probucol the serum concentration ranged from 10 to 182
µmol/L, with a mean value of 60 µmol/L. Serum probucol decreased
rapidly in the placebo group, but it did not reach zero even after 3
years.
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Serum Concentrations of Diet-Derived Antioxidants
The serum concentrations of vitamin E, ß-carotene, lycopene, and
vitamin A during cholesterol-lowering therapy are given in
Fig 3. -Carotene concentration paralleled
that of ß-carotene. During the prerandomization phase there were no
significant differences in serum antioxidants between the treatment
groups. Diet therapy resulted in a slight increase in serum
antioxidants, both treatment groups taken together, that was only
significant for vitamin E (P<.05). After 2 months on
cholestyramine, the mean serum vitamin E decreased by 7%
(P<.001), ß-carotene by 40% (P<.001), and
lycopene by 30% (P<.001), whereas vitamin A increased by
5% (P<.001). The addition of probucol to the regimen
resulted in an additional significant decrease of the concentration of
vitamin E by 14%, ß-carotene by 39%, and lycopene by 30% (all
P<.001). Thus, the combined effects of cholestyramine and
probucol were to reduce vitamin E by 18%, ß-carotene by 65%, and
lycopene by 51%, relative to their pretreatment values.
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After randomization the serum concentrations of vitamin E, - and
ß-carotene, and lycopene increased significantly (all
P<.001) in the placebo group, returning to the pre-probucol
level (see Fig 3
). For vitamin E this occurred within 6 months, but it
took 1 to 2 years for lycopene and ß-carotene to return to their
pre-probucol levels. The vitamin A concentration decreased steadily
throughout the trial in both treatment groups (see Fig 3). Serum
vitamin A was 11% lower in the placebo group at the end of the study
compared with the beginning of the study (P<.001).
The results of multiple regression analyses are
presented in Table 2. Probucol and
cholestyramine were not significant predictors of serum vitamin E after
adjustments for lipids were made. Another way of demonstrating this
finding was to express serum vitamin E relative to serum
cholesterol plus triglycerides. We found a
steady increase in this ratio, from 4.5 to 5.5 µmol vitamin E per
mmol lipids, during the prerandomization phase when all patients were
given the same treatment. After randomization the two treatment groups
had almost identical values, 
5.4 µmol/mmol, throughout the study.
In contrast, significant negative and lipid-independent effects of
cholestyramine and/or probucol were found on serum ß-carotene and
lycopene. Essentially the same results were obtained in additional
statistical models, taking into account the possibility that the
associations between serum antioxidants and serum lipids changed over
time.
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The mean concentrations of diet-derived antioxidants were higher in all
lipoproteins in the placebo group compared with the probucol group
(Table 3). Because of the limited number of samples the
differences were not statistically significant in all cases. Patients
in the probucol group displayed a shift of antioxidants from HDL to LDL
when expressed as a percentage of the total content in lipoproteins
(shown in parentheses in Table 3). When expressed as molecules per gram
of protein, probucol was the major antioxidant in all lipoprotein
classes in the probucol group.
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The associations between serum antioxidant concentrations and
lipoprotein lipids were analyzed. Both vitamin E
(P<.001) and ß-carotene (P<.01) correlated
positively with LDL cholesterol throughout the study.
However, only -carotene (P<.05) and ß-carotene
(P<.001) correlated positively with HDL
cholesterol. We found that ß-carotene correlated
positively with HDL2b, expressed as its serum
protein concentration (r=.35, P<.01, n=61,
before lipid lowering), whereas with HDL3b the association
was negative (r=-.32, P<.05, n=61). In contrast
to the carotenes, vitamin E correlated positively (P<.001)
with apoB, the concentration of which is proportional to the number of
LDL particles, throughout the trial. LDL particle size was estimated as
the ratio of LDL cholesterol to apoB, with a larger value
indicating a larger particle. Serum vitamin E was negatively but
nonsignificantly associated with this ratio at all times, whereas
ß-carotene showed a positive and consistent association
(P<.01) with LDL particle size. Positive relationships were
also found between LDL particle size and -carotene and lycopene, but
they were weaker than for ß-carotene. At the end of the trial the HDL
protein concentration was significantly lower (P<.001) in
the probucol group (n=35) compared with the placebo group (n=37); in
particular, the HDL2b concentration was 69% lower
(P<.001). Furthermore, the apoB concentration was 8% lower
in the probucol group and the LDL cholesterol–apoB ratio
was 5% lower (P<.05) than in the placebo group. Thus,
probucol treatment resulted in major reductions in HDL particle number
and size and in minor reductions in LDL particle number and size.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The main finding of the present study was that probucol, an antioxidant drug, reduced the serum concentrations of diet-derived lipid-soluble antioxidants in hypercholesterolemic patients with established atherosclerotic disease. According to the oxidation hypothesis of atherosclerosis development,8 the opposite result was expected, namely, that probucol should protect the natural antioxidants against oxidation and thus lead to higher serum levels of these substances. The lowering of serum levels of the antioxidants was not caused by dietary differences between the treatment groups. To our knowledge there are no data suggesting that probucol could act as a pro-oxidant in vitro or in vivo. Therefore, the mechanism whereby probucol lowered the serum concentrations of diet-derived antioxidants must be unrelated to its antioxidant properties.
Serum vitamin E decreased in response to lipid lowering induced by cholestyramine and probucol. In agreement with our results, Paterson et al23 found no change in plasma vitamin E relative to cholesterol in a small uncontrolled probucol trial lasting for 16 weeks. The reductions in serum carotenoids in our trial were larger than could be explained by lipid lowering alone. The most likely explanation for the effect of cholestyramine was that it reduced the intestinal absorption of the lipophilic carotenoids, because cholestyramine is known to decrease the absorption of lipids.24
The reductions in both HDL and LDL particle size induced by probucol
were clearly undesirable, because small particles are associated with
an increased risk of atherosclerosis.7 25
Serum carotenes, but not vitamin E, were found to correlate positively
with LDL and HDL particle size. The reason for this difference is
probably based on differences in polarity of vitamin E and the
carotenes. ß-Carotene, which is more hydrophobic than vitamin E and
probucol, is likely to be located in the lipoprotein
core,26 whereas vitamin E and probucol probably distribute
throughout a lipoprotein particle and are therefore less dependent on
the core size. It has previously been shown that the ß-carotene
content of bovine HDL is dependent on particle size, being absent from
particles with diameters less than 10 nm.27 According to
our data the average number of probucol and vitamin E molecules per HDL
particle is 1, if it is assumed that the molecular weight of a
particle is 250 kD and that 50% of its mass is protein.12
In contrast, only 1 out of 150 to 400 HDL particles contained 1
molecule of lycopene and ß-carotene. There were 16 molecules of
probucol and 11 molecules of vitamin E per LDL particle if it is
assumed that the molecular weight of LDL is approximately 2500 kD and
the protein content is 22%.28 Lycopene and ß-carotene
would be found in approximately every fifth LDL particle. Taken
together these data demonstrate that particle size and number are
important determinants of the content of lipid-soluble antioxidants.
For vitamin E, particle number is decisive, whereas for the carotenes
the size of a particle is the most important factor. The serum
concentration of probucol, which lowers primarily HDL
cholesterol, appears also to be a function of lipoprotein
lipids and particle number.
In the present study there was a 35% reduction in HDL cholesterol because of therapy with probucol, whereas LDL cholesterol was only reduced by 3%.5 The reduction in HDL mass by probucol resulted in a shift of antioxidants toward LDL, confirming previous in vitro findings that HDL will readily donate vitamin E to LDL and VLDL if the ratio of HDL to LDL is decreased.12
Another mechanism whereby probucol may reduce serum carotenoids takes
place during VLDL assembly in the liver. There is little discrimination
between the tocopherols (all vitamin E isomers) and the
carotenes during absorption and chylomicron formation in intestinal
cells. However, in the liver there is a preferential incorporation of
RRR--tocopherol, the naturally occurring
stereoisomer of vitamin E, into VLDL. This is due to the
stereoselectivity of the hepatic tocopherol transfer
protein.29 Once located in VLDL, hydrophobic molecules are
more or less trapped in apoB-containing lipoproteins during the
conversion to LDL. However, some surface components and core lipids
(including antioxidants) are transferred directly from chylomicrons to
HDL.13 26 Carotenoids and other tocopherol
isomers that remain in chylomicron remnants on their way to the liver
are incorporated into VLDL in a nonspecific manner,26 and
it can be reasonably assumed that this is also the case for probucol.
Our results nevertheless show that probucol was very efficiently packed
into VLDL, thereby probably displacing the carotenoids.
The steady decline in the serum vitamin A concentration in both treatment groups during the trial was probably caused by interference of cholestyramine with intestinal absorption of vitamin A and/or its precursor ß-carotene. Probucol therapy resulted in an additional reduction of serum vitamin A by 8% to 10%. This was most likely explained by the 10% lowering of serum triglycerides by probucol, because some vitamin A associates with triglyceride-rich lipoproteins.10 Therefore, hypertriglyceridemic patients display elevated serum vitamin A levels,9 and variations in serum triglycerides are mirrored by changes in serum vitamin A.
In conclusion, probucol lowered the serum concentrations of diet-derived antioxidants most likely by reducing lipoprotein particle number and size. In addition probucol competed with carotenoid substances for incorporation into VLDL in the liver. Our findings emphasize the importance of lipoprotein particle size as one predictor of serum ß-carotene concentration. This is of great importance when comparing serum carotenoids in patients at risk of cardiovascular disease, who are known to display differences in lipoprotein particle size. Whether or not these changes in lipid-soluble antioxidants in the probucol group had any influence on the outcome of the trial is subject to further analysis.
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Acknowledgments |
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This work was funded by the Marion Merrell Dow Research Institute, Kansas City, Mo, the Swedish Margarine Industrial Association for Nutritional Research, the King Gustaf V 80th Birthday Fund, the Nanna Swartz Fund, and the Swedish Medical Research Foundation No. 06962. The excellent technical assistance of Malin Liljeström and Kerstin Carlson is gratefully acknowledged. We are also grateful to Inger Malmaeus and Björn Gustafsson at Sema Group InfoData AB.
Received March 15, 1995; accepted May 30, 1995.
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