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*
Department of Biochemistry, Stockholm University, S-106 91 Stockholm, Sweden and
Clinical Research Center and
**
Department of Molecular Medicine, Karolinska Institutet, S-171 76, Stockholm, Sweden
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • coenzyme Q • rats • blood lipids • aging
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Three main
functions are attributed to this lipid, depending on distribution and
concentration. It is a redox component of the mitochondrial respiratory
chain; this electron carrier role was considered for a long time to be
its only function (Trumpower 1990
). However, its broad
distribution provides a clue to its additional cellular role as the
only endogenously synthesized lipid-soluble antioxidant
(Ernster 1993
). CoQ is highly efficient in preventing
lipid, protein and DNA oxidation, and it is continuously regenerated by
intracellular reduction systems (Andrée et al. 1998
). In liposomes and in a mixture consisting of
lipoproteins, it was demonstrated that CoQ is preferentially utilized
as an antioxidant when both this lipid and 
-tocopherol are available
(Frei et al. 1990
, Stocker et al. 1991
).
In model membranes, CoQ destabilizes membranes and increases fluidity
and permeability (Quinn and Katsikas 1985
).
The tissue concentration of CoQ changes in physiologic processes such
as during exercise and cold acclimation (Beyer et al. 1962
, Mataix et al. 1997
). Its amount decreases
in cardiomyopathy, degenerative muscle diseases, hepatocellular cancer
and in most tissues during aging (Eggens et al. 1989
,
Kalén et al. 1989
, Karlsson et al. 1990
, Mortensen 1993
). In neurodegenerative
diseases, such as Alzheimer’s and prion disease, its concentration is
significantly elevated in the brain (Guan et al. 1996
,
Söderberg et al. 1990
). In some pathologic
processes, when tissue CoQ content is decreased, it may be advantageous
to supplement CoQ by dietary administration. Exogenously administered
CoQ10 has an important function in the blood when
free radical production is elevated, such as in
ischemia-reperfusion syndrome, inflammation and conditions in which
cholesterol and cholesterol ester oxidation occurs (Haramaki et al. 1998
, Tribble et al. 1994
, Upston et al. 1997
).
In both experimental and human studies, dietary
CoQ10 has been shown to be taken up into the
blood and distributed in LDL and HDL (Elmberger et al. 1989
, Mohr and Stocker 1994
). Uptake into the
liver is also substantial. Conversely, uptake into the kidney, heart,
muscle and brain does not occur in rats administered
CoQ10 (Alessandri et al. 1988
,
Lönnrot et al. 1998
, Reahal and Wrigglesworth 1992
, Zhang et al. 1995
and 1996
).
However, in a recent study, it was found that
CoQ10 is taken up into the brain; in addition,
the exogenous lipid also greatly elevates the concentration of
endogenously synthesized CoQ9 (Matthews et al. 1998
).
The role of -tocopherol as a lipid-soluble antioxidant is well
documented, and the efficiency of the uptake process can be greatly
elevated by derivatization of this vitamin (Burton et al. 1988
). Our aim was to investigate the possible improvement of
CoQ10 uptake after esterification and
administration of the acetylated and succinylated forms. It appeared
possible to perform experiments by analyzing lipids with the available
HPLC methodology because it can separate the CoQ9
(endogenous) and CoQ10 (dietary) species. Our
purpose was to establish whether derivatization increases the uptake
into the blood and whether these derivatives are taken up by various
organs. Because the major part of CoQ in all tissues is synthesized by
the tissues themselves, uptake of exogenous lipid may down-regulate
this biosynthetic process by a feedback mechanism, if the exogenous
lipid is distributed into appropriate compartments. If
down-regulation of endogenous synthesis occurs, dietary
administration of CoQ would not be meaningful. Therefore, the
endogenous CoQ9 synthesized during dietary
treatment is of considerable interest.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Sprague-Dawley rats (Anticimex, Stockholm, Sweden) were used.
The diet was composed of cereal products (barley, wheat feed, wheat,
corn germ), vegetable proteins (high protein soybean), animal proteins
(Chilean fish meal) and a vitamin
mixture.3
The CoQ concentration in this diet was < 0.1 mg/kg. The
CoQ-enriched diet contained one of the following: CoQ10
(Sigma Chemical, St Louis, MO) (1g/kg diet), acetylated
CoQ10 (1 g/kg diet) or succinylated CoQ10 (1
g/kg diet). Diacetylated and disuccinylated CoQ10 were
synthesized according to Okamoto et al. 1985
and
provided to us by E. Blackedal (Vulpes, Göteborg, Sweden). The
chemical structures of CoQ10 and its acetylated and
succinylated forms are shown in Figure 1
. The purity and identity of these compounds were verified by gas
chromatography/mass spectrometry and 1H and 13C
nuclear magnetic resonance (Vulpes). The ethics committee of the
university approved the experiments in this study.
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Rats (6 wk old), weighing 180 ± 6 g, were divided randomly into four groups. The control group received the basal diet. The diet mixed with CoQ10 was given to the second group. The third group received the acetylated CoQ10, and the fourth group was given succinylated CoQ10 mixed into the diet. All groups had free access to their respective diets, and the treatments were continued for 3 wk. At the end of the treatment, body weights were measured; the mean weight of rats in both the control and treated groups increased to 320 ± 10 g. Rats were decapitated and liver, kidney, heart, muscle, brain and spleen were removed and stored at -20°C for later analysis. Blood was taken for the preparation of plasma.
Experiment 2.
Rats weighing 180 ± 6 g were divided into three groups and given free access to the basal diet. The first group was the control rats. The second group received succinylated CoQ10 by intraportal administration. The rats were anesthetized by intraperitoneal injection of 0.1 mL Mebumal (60 mg/mL) per 100 g body weight. The succinylated CoQ10 (10 mg) was mixed with 0.3 mL Intralipid (Pharmacia & Upjohn, Uppsala, Sweden) by sonication and injected into the portal vein. After 30 min, the rats were decapitated, blood was collected, and the heart and liver removed. The third group of rats was injected intraperitoneally with succinylated CoQ10, prepared as described above. Three injections were made at 12-h intervals (3.3 mg succinylated CoQ10 each time, dissolved in Intralipid) and the rats were decapitated 12 h after the last injection. Blood, heart and liver samples were removed.
Experiment 3.
Male Sprague-Dawley rats (12 mo old), weighing 420 ± 5 g, were divided into two groups. The first group was the control and the second group received CoQ10 for 3 wk as described in Experiment 1. The weight of both groups increased to 435 ± 6 g. Rats were decapitated and liver, kidney, muscle, spleen, heart and brain were removed; blood was taken for the preparation of plasma.
Preparation of hepatic subfractions.
Livers were homogenized in 0.25 mol/L sucrose with three strokes in a Potter-Elvehjem homogenizer at 440 rpm The homogenate was then centrifuged at 300 x g for 10 min. The resulting supernatant, called "300 x g supernatant" was centrifuged at 6000 x g for 20 min. The pellet (mitochondria) was washed three times and resuspended in 0.25 mol/L sucrose (1 g liver/mL). The supernatant after the 6000 x g centrifugation was collected and named "postmitochondrial supernatant."
Lipid extraction.
Tissues were homogenized in 0.25 mol/L sucrose in an Ultra Turrax
blender (IKA Labortechnik, Staufen, Germany). One milliliter of
homogenate, hepatic subfraction or blood was supplemented with 10 nmol
CoQ6 (Sigma Chemical) as an internal standard. Samples were
then extracted with 18 mL methanol and 12 mL petroleum ether (boiling
point 40–60°C) as described by Åberg et al. 1992
.
After extensive vortex treatment for 30 s, the petroleum ether
phase was collected and evaporated under N2. The residue
was dissolved in 50 µL chloroform/methanol (2:1) and
stored at 4°C in the dark. The samples were analyzed 20 h later
by HPLC (Shimadzu LC-10A system, Shimadzu, Tokyo, Japan). At the time
of measurement, all of the CoQ was in an oxidized form.
Analysis of CoQ by HPLC.
Analyses were carried out using a reversed-phase ODS Hypersil C18,
3-µm column (Hewlett-Packard, Böblingen,
Germany) as described by Ericsson et al. 1991
. CoQ
levels were quantified by employing a linear gradient starting from
methanol/water (9:1) (solvent A) to
methanol/2-propanol/n-hexane (2:1:1) (solvent B) with a
program time of 45 min and a 1.5 mL/min flow rate according to
Ericsson et al. 1992
. The absorption was monitored with
a UV detector (Waters model 490, Millipore, Bedford, MA) at 210 and 275
nm. CoQ9 and CoQ10 were identified with
standards and by reduction of the isolated fractions with sodium
borohydride. With HPLC, CoQ9 and CoQ10
exhibited a baseline separation, and detection at 275 nm did not result
in coelution of other disturbing substances (Fig. 2
). The elution time for CoQ9 and CoQ10 was 18
and 22 min, respectively.
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Data are presented as means ± SEM. The differences
between the two groups (Tables 1
and 2)
were evaluated by Student’s
t test. For comparison of several groups or for repeated
comparisons to a single control group (Figs. 3
and 4)
, ANOVA and
Dunnett’s post-hoc test were used. The statistical analyses were
performed with GraphPad Instat Version 3.01 (GraphPad Software, San
Diego, CA). Differences were considered significant at P
< 0.001 after Bonferroni correction.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The endogenous CoQ10 level in the control group
was 51.6 nmol/L and increased to 1440.6 nmol/L when the nonderivatized
lipid was consumed. Rats fed acetylated CoQ10 had
blood concentrations exceeding 2240 nmol/L (P < 0.001). The succinylated derivative was absorbed less efficiently than
the acetylated form, but the uptake was 40% higher than that of the
nonderivatized CoQ. The uptake of CoQ10 into the
liver was also highly efficient. The concentration in the liver of
control rats was 3.8 nmol/g, whereas in rats fed
CoQ10, the concentration was 146 nmol/g (Fig. 3A
). Both the acetylated and succinylated forms of
CoQ10 were efficiently taken up by the liver, but
in contrast to the situation in the blood, the derivatization did not
further increase the uptake levels. In both blood and the liver,
endogenous CoQ10 did not represent more than
~10% of the total. Because administration of an exogenous substance
may influence the biosynthetic rate of the endogenous lipid, the level
of CoQ9, was determined. Administration of
CoQ10 or its esterified derivatives did not
affect the endogenous CoQ9 concentration in the
blood or the liver.
In brain and heart, dietary treatment had no effect on the endogenous
CoQ10 concentration (Fig. 3B
). The
dietary treatments did not influence the endogenous
CoQ9 concentrations in either the brain or the
heart, where this lipid species comprises 60 and 90% of the total,
respectively.
In kidney and muscle, no uptake was observed upon administration of
CoQ10 or its esterified forms (Fig. 3C
). However, the rats treated with dietary
CoQ10 had an eightfold greater concentration of
this lipid in the spleen than did the nontreated control. The levels in
rats administered the acetylated and succinylated forms were similar.
The spleen is a blood-rich organ; however, this does not explain
the relatively high level of CoQ10 after dietary
treatment. The endogenous CoQ9 concentration in
muscle, kidney and spleen tissue made up 90, 80 and 70% of the total,
respectively, but administration of CoQ10 or its
derivatized forms did not affect the level of the
CoQ9.
The presence of acetylated and succinylated forms of CoQ10 in blood and organs was analyzed with HPLC because these derivatives have a shorter elution time than that of the nonderivatized form. In blood, ~5% of the total uptake of the lipid could be identified as the derivative, whereas in liver and spleen, no succinylated or acetylated forms were detected (not shown). Esterases present in both blood and various tissues appear to efficiently hydrolyze the derivatized forms of CoQ10.
The intracellular localization of exogenous CoQ10
was investigated by fractionation of the liver homogenate. In liver of
the controls, mitochondria represented the largest membranous cellular
compartment; ~80% of the total cellular CoQ10
was present in mitochondria, whereas the remainder was distributed in
the other subcellular membranes, present in the postmitochondrial
supernatant (Fig. 4A
). A similar distribution pattern was also found for
CoQ9 (not shown). Treatment of rats with
CoQ10 or its acetylated or succinylated forms
increased the lipid concentration in both mitochondria and the
postmitochondrial supernatant. However, this elevation was greater in
the latter fraction than in the mitochondria (Fig. 4B
).
Thus, the CoQ distribution pattern (CoQ9 and
CoQ10)
in these two compartments after treatment was the
opposite of that found in the control rats, and the majority of the
CoQ10 was distributed in the extramitochondrial
compartment.
We investigated whether the route of administration is the main cause
of restricted uptake of CoQ10 into blood, liver
and spleen but not into other organs. For this reason, succinylated
CoQ10 was injected directly into the portal vein
instead of peroral administration (Table 1
). In the liver, the concentration of CoQ10 was
six times greater than that in the control group after 30 min, but in
the heart, no detectable uptake of this lipid was observed. In rats
given intraperitoneal injections of succinylated
CoQ10, efficient uptake into the liver was found,
and the lipid concentration was eight times greater than that in
controls. Again, this administration method did not affect the
CoQ10 concentration of the heart.
The possibility was tested that in older rats, which have a lower
concentration of CoQ in most organs compared with younger ones, the
lack of optimal tissue concentration may activate the uptake mechanism
and the lipid would be more easily absorbed from the diet (Table 2
). The CoQ10 concentration in blood was ~20
times greater in the CoQ10-supplemented group
than in controls. In the liver, the elevation was 30-fold, whereas in
the spleen, the lipid concentration was eight times higher in the
treated rats. In brain, heart, kidney and muscle, the lipid
concentration in the two groups did not differ, showing the lack of
uptake from the diet. Also, the endogenous CoQ9
levels were unchanged in all tissues investigated. The results obtained
with the older rats are similar to those described for the younger rats
in Figure 3
, demonstrating that uptake of dietary
CoQ10 is not age dependent.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In contrast to
other neutral lipids, this lipid decreases with aging in most organs in
both experimental systems and humans (Beyer et al. 1985
, Kalén et al. 1989
). Lowered
concentration may appear in a number of tissues in various diseases but
is most often observed in the heart and muscle. Because the two main
lipid-soluble antioxidants of the blood are -tocopherol and CoQ,
it is not surprising that both of these antioxidants efficiently
prevent oxidative stress-induced damage in conditions such as
ischemia-reperfusion syndrome (Haramaki et al. 1998
).
When tissue concentrations of CoQ in experimental systems and humans
are low, dietary administration of this lipid is often applied
(Folkers 1990
). Uptake into the blood is dependent on
various factors such as the various oils in the mixture, other dietary
constituents and the physical properties of CoQ administered.
Administration of a derivatized lipid is often used to increase the
uptake and transport efficiency. During the uptake of cholesterol,
esterification with a fatty acid occurs in the intestinal wall;
dolichol is esterified in a similar manner to make possible its
intracellular transport to the lysosomes (Kahn et al. 1989
, Tollbom et al. 1988
). -Tocopherol used
in supplementation is acetylated or succinylated, and these esterified
forms of CoQ were applied in this study. Derivatization of CoQ improved
the efficiency of uptake, and the blood levels were significantly
increased with both derivatives, particularly the acetylated form.
Because uptake into the liver and spleen takes place efficiently with
the nonderivatized form, it is not expected that modification of the
natural substance is required in this case. In our study and those
preformed previously, there was no appreciable uptake of dietary CoQ by
kidney, heart, muscle and brain tissues. These findings are at variance
with those found in a recent study in which the brain concentration of
CoQ was greater in rats after dietary supplementation (Matthews et al. 1998
).
There are several possible explanations for the lack of uptake observed here, in addition to the most obvious cause, i.e., the absence of a transport mechanism for this specific substance. Uptake may be dependent on the dose and length of exposure employed. In our experiments, the CoQ supply exceeded that generally given to human subjects 20–30 times; therefore a further increase of the dietary content did not appear meaningful. The fact that the total CoQ concentration of both blood and liver was increased several-fold in our investigation proves that efficient uptake occurred when the transport mechanism was operative.
CoQ is a membrane constituent, and it is not obvious that dietary
intake increases its concentration in membranes. The polyisoprenoid
portions of CoQ, dolichol and dolichyl phosphate, are considered to be
situated in the central hydrophobic portion of the membrane bilayer,
which can house only a limited amount of these lipids (de Ropp and Troy 1985
, Valtersson et al. 1985
). Accordingly, for uptake studies,
membranes with a lipid deficiency could be more appropriate.
One-year-old rats have lower CoQ concentrations in most tissues than
younger rats. When these older rats were used in the uptake studies,
the results were similar to those of the younger age group. Therefore,
it is unlikely that the lack of uptake in some of the organs studied
was due to the use of younger rats with a higher endogenous CoQ
concentration. Because high uptake of CoQ was observed in both the
liver and spleen, the idea that uptake requires deficiency is not
supported. In the liver, exogenous CoQ was increased in both
mitochondria and other membranes, but it remains to be established
whether it was incorporated into the appropriate intramembraneous
compartment. It is possible that the major proportion of the
derivatized lipid was hydrolyzed during uptake into the blood, which
may result in an inefficiency of transport into other tissues. However,
because neither intraportal nor intraperitoneal administration gave
better results than the peroral supplementation, this possibility
appears to be unlikely.
Administration of particular compounds often down-regulates endogenous synthesis, which is very unfavorable. If the uptake of exogenous CoQ is paralleled by a decrease in the endogenous cellular CoQ, the dietary supplementation is not effective. In our experiments, no decrease of CoQ9 levels was found in the liver and spleen, in spite of the fact that CoQ10 levels were increased many-fold. This is a favorable observation, suggesting that the search for new ways to increase the CoQ concentration in various organs is not futile.
A large number of studies in the literature propose substantial
functional improvement in organs upon CoQ administration, in spite of
the limited uptake of this lipid. This limitation, however, does not
exclude the possibility that CoQ modifies organ functions. Upon
metabolism of CoQ, as well as after irradiation or concomitant lipid
peroxidation, a number of intermediates and metabolites are produced
that could have direct regulatory effects on the biosynthetic process
(Forsmark-Andrée et al. 1997
, Morimoto et al. 1969
). Alternatively, interaction with cell surface
receptors can activate intracellular signaling mechanisms such as
heterotrimeric G-proteins, which could explain the positive effects
observed. Isolation and characterization of these metabolites are
clearly important tasks for the future.
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FOOTNOTES |
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3 The protein content was 18.7 g, the fat content 4 g and carbohydrates, 57 g/100 g. The vitamin mixture
consisted (per 100 g) of retinol (1460 IU), cholecalciferol (150 IU), -tocopherol (10
µg), thiamin (1.3 mg), riboflavin (1.2 mg), pyridoxine (1.4 mg), menadione (1.6 mg), B-12 (3.1 µg), folic
acid (0.28 mg), nicotinic acid (7.8 mg), pantothenic acid (2.6 mg), choline (139 mg), inositol (171 mg) and biotin (36
µg). The major minerals were (per 100 g) calcium (0.74 mg), phosphorous (0.71 mg), sodium (0.22 mg), chlorine (0.45 mg),
magnesium (0.18 mg) and potassium (0.70 mg). The trace minerals consisted of iron, copper, manganese, zinc, cobalt, iodine and selenium.
Manuscript received March 31, 1999. Initial review completed April 28, 1999. Revision accepted July 27, 1999.
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