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Department of Nutrition and Food Science, and Kentucky Agricultural Experiment Station, University of Kentucky, Lexington, KY 40506;
*
Hoffmann-La Roche Incorporated, Nutley, NJ 07110; and
Tishcon Corporation, Westbury, NY 11590
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-tocopherol equivalent) supplemented with either
0 or 500 mg CQ10, and 0, 100 or 1310 IU VE/kg diet for 14
or 28 d. Liver, spleen, heart, kidney, skeletal muscle, brain and
serum were analyzed for the levels of CQ10, CQ9 and VE. CQ10
supplementation significantly (P < 0.05) increased
CQ10 concentration in the liver and spleen (total and mitochondria) and
serum, but not in other organs. Interestingly, rats supplemented with
CQ10 plus 100 IU VE/kg diet had significantly higher CQ10
levels in the liver and spleen, whereas those supplemented with CQ10
plus 1310 IU VE/kg diet had lower levels, compared with
those supplemented with CQ10 alone. As expected, dietary VE increased
VE content in all of the organs analyzed in a dose-dependent
manner. However, rats fed the basal diet supplemented with CQ10 had
significantly higher VE levels in liver (total and mitochondria) than
those not receiving CQ10 supplementation. CQ9 levels were higher in the
liver and spleen, lower in skeletal muscle and unaltered in brain,
serum, heart and kidney of rats supplemented with CQ10 compared with
the controls. These data provide direct evidence for an interactive
effect between exogenously administered VE and CQ10 in terms of tissue
uptake and retention, and for a sparing effect of CQ10 on VE. Data also
suggest that dietary VE plays a key role in determining tissue
retention of exogenous CQ10.
KEY WORDS: • coenzyme Q10 • vitamin E • mitochondria • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Maltese and Aprille 1985
), which is also involved in
cholesterol biosynthesis. The predominant form of CQ in humans is CQ10,
which contains 10 isoprenoid units, whereas the main form in rodents is
CQ9, which has nine isoprenoid units.
CQ is an essential cofactor in the mitochondrial electron transport
chain where it accepts electrons from complexes I and II (Beyer 1992
, Ernster and Dallner 1995
). CQ also
functions in its reduced form (ubiquinol) as an antioxidant, protecting
biological membranes (Forsmark-Andree et al. 1997
,
Noack et al. 1994
). Effective protection against
oxidative damage by CQ10 has been demonstrated in liposomes, LDL,
biological membranes, proteins and DNA (Forsmark et al. 1991
, Forsmark-Andree and Ernster 1994
,
Stocker et al. 1991
). Decreases in CQ10 levels have been
reported in cardiomyopathies, degenerative muscle diseases and during
aging (Battino et al. 1995
, Kalen et al. 1989
, Karlsson et al. 1990
, Mortensen 1993
). Most of the clinical work with CQ10 has focused on heart
disease, specifically congestive heart failure and cardiomyopathy. The
majority of the studies showed that treatment with CQ10 improved heart
muscle function significantly without known adverse effects
(Langsjoen et al. 1994
). In addition to heart disease,
the beneficial effects of CQ10 also have been demonstrated in patients
with mitochondrial disorders (Bresolin et al. 1988
,
Ihara et al. 1989
, Nishikawa et al. 1989
,
Shoffner et al. 1989
).
Vitamin E (VE) is the major lipid-soluble chain-breaking
antioxidant found in plasma, red cells and tissues, and plays an
essential role in maintaining the integrity of biological membranes
(Burton and Traber 1990
, Chow 1991
). VE
can also react directly with peroxyl and superoxide radicals
(Fukuzawa and Gebicki 1983
, Niki et al. 1984
). VE is functionally interrelated with a number of
antioxidants, including ascorbic acid, glutathione, lipoic acid and CQ
(Chan et al. 1991
, Kagan et al. 1990
,
Maguire et al. 1992
, McCay 1985
,
Niki et al. 1982
, Packer et al. 1997
).
High concentrations of both CQ and VE are found in the inner
membranes of mitochondria. The possibility of interaction
between CQ and VE in terms of VE recycling was first suggested in the
1960s (Mellors and Tappel 1966
). However, the bulk of
the experimental evidence available concerning the interaction between
these two compounds is derived from in vitro studies (Kagan et al. 1990
, Lass and Sohal 1998
, Maguire et al. 1992
, Mellors and Tappel 1966
,
Stoyanovsky et al. 1995
).
A number of studies have examined the interaction between VE and CQ10
with inconsistent findings. For example, Zhang et al. (1995
and 1996)
showed that dietary CQ was taken up only into liver,
spleen and plasma, and not into kidney, heart, muscle and brain; VE
supplementation increased the levels of both endogenous and exogenous
CQ in the liver and plasma, whereas dietary CQ10 had no effect on
tissue VE. On the other hand, Lass et al. (1999)
found
that mice treated orally with CQ10 had higher CQ10 levels in the serum,
liver and kidney, and higher VE levels in the mitochondria of skeletal
muscle and liver. They also found that mice treated orally with both VE
and CQ10 had lower CQ10 in liver mitochondria compared with those
supplemented with CQ10 alone. To gain a better understanding of the
interaction between VE and CQ10, we examined the influence of
exogenously administered CQ10 and VE on the concentrations of exogenous
and endogenous CQ and VE in rat tissues and mitochondria.
|
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mono- and di-basic sodium phosphate were purchased from Fisher Scientific, Cincinnati, OH. HPLC-grade methanol and hexane were purchased from EM Science, Gibbstown, NJ. Ethanol (95%) was obtained from Midwest Grain Products, Pekin, IL. Potassium ferricyanide was purchased from J. T. Baker Chemicals, Phillipsburg, NJ. KCl, EDTA, Nagarse, Tris-HCl, Tris base, sucrose, Folin’s reagents, copper sulfate, sodium tartrate, sodium carbonate and sodium hydroxide were purchased from Sigma Chemical, St. Louis, MO.
Diets and feeding regimen.
Dietary ingredients were purchased from Dyets, Bethlehem, PA. The basal
diet (AIN-93M) consisted of 14.00% vitamin-free casein, 46.57%
cornstarch, 15.50% dextrose, 10.00% sucrose, 5.00% cellulose, 4.00%
soybean oil, 3.50% salt mix, 1.00% vitamin mix (without VE), 0.18%
DL-methionine and 0.25% choline bitartrate (Reeves et al. 1993
). Soybean oil (4%) in the basal diet provided
10 IU VE (6.7 mg RRR--tocopherol
equivalent)/kg diet. Diet 1 was the basal diet without any
supplementation. Diet 2 was the basal diet supplemented with 500 mg
CQ10/kg diet. Diet 3 was the basal diet supplemented with 500 mg
CQ10/kg diet and 100 IU VE (as
RRR--tocopherol)/kg diet. Diet 4 was the basal diet
supplemented with 500 mg CQ10/kg diet and 1310 IU VE/kg
diet. Male Sprague-Dawley rats (n = 32; 12 mo
old; Harlan Sprague Dawley, Indianapolis, IN) were assigned randomly to
the four diets (n = 8/group). Food and water were
consumed ad libitum. Four rats from each group were killed after
consuming their respective diets for 2 wk; the rest were killed at 4
wk. The experimental protocol was reviewed and approved by the
University of Kentucky Institutional Animal Care and Use Committee.
Sample preparation.
At the end of each feeding period, rats were killed after blood
withdrawal via heart puncture. Liver, spleen, heart, kidney, skeletal
muscle and brain were immediately removed, blotted and weighed.
Portions of liver, spleen and heart were processed and prepared for
isolation of mitochondria (Bhattacharya et al. 1991
). Immediately after killing, the heart was thoroughly
minced and incubated with 5 volumes of 0.2 mol/L Tris-HCl buffer
containing 20 g/L Nagarse, 100 mmol/L sucrose, 10 mmol/L
ethylenediaminetetraacetate, 46 mmol/L KCl and 5 g/L bovine serum
albumin, pH 7.4 (Buffer A) at room temperature for 5 min. After the
incubated minced tissue was washed with the same buffer without Nagarse
(Buffer B), a 100 g/L homogenate was prepared with Buffer B using a
Tekmar tissuemizer (Tekmar, Cincinnati, OH). After incubation, the
homogenate was centrifuged at 500 x g for 10 min,
and the supernatant was centrifuged at 12,000 x g
for 10 min. The resulting pellet was suspended in Buffer B and
centrifuged at 12,000 x g for 10 min. The pellet,
which is the mitochondria fraction, was resuspended in Buffer B. Liver
and spleen mitochondria were prepared using Buffer B without treatment
with Nagarse. Another homogenate was prepared in ice-cold 1.55
mol/L KCl in 0.05 mol/L phosphate buffer, pH 7.4, for measuring the
levels of CQ10, CQ9 and VE.
Biochemical measurements.
The lipid extract was measured for the levels of VE (-tocopherol) by
an HPLC procedure using a fluorescence detector with excitation at 205
nm and emission at 340 nm (Hatam and Kayden 1979
). The
levels of both CQ10 and CQ9 were measured according to the HPLC
procedure of Okamoto et al. (1985)
using UV detection at
275 nm. The mitochondrial protein concentration was measured using
Folin’s reagent (Miller 1959
).
Analysis of data.
Data obtained were analyzed using ANOVA followed by Tukey’s multiple comparison test. The windows version of SYSTAT 5 software (SYSTAT, Evanston, IL) was employed.
|
RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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CQ10 supplementation for 14 or 28 d significantly (P
< 0.05) increased the CQ10 concentration in the liver, spleen and
serum (Table 1
) compared with the group not supplemented with CQ10. The increases in
CQ10 concentrations were relatively larger in the liver and spleen of
rats fed the experimental diets for 28 d than in those fed for
14 d. The levels of CQ10 in the heart, kidney, skeletal muscle and
brain (Table 1)
were not significantly altered by CQ10 supplementation
for 14 or 28 d. Similar to the effect in the whole organs, dietary
CQ10 significantly increased the CQ10 level in the mitochondria of
liver (Fig. 1A
) and spleen (Fig. 1B
), but not heart (Fig. 1C
).
|
|
of rats supplemented with 100 IU VE/kg diet for
either 14 or 28 d than in those of the controls. On the other
hand, rats supplemented with 1310 IU VE/kg diet had
significantly lower CQ10 levels in the liver and spleen than the
respective controls. The increases of CQ10 concentration were
relatively larger in the liver and spleen of rats supplemented with 100
IU VE/kg diet for 28 d than in those fed for 14 d. The CQ10 concentrations of serum, heart, kidney, skeletal muscle and
brain (Table 1)
were not significantly altered by dietary VE at any
dose. Similar to the effect in the whole organs, supplementing 100
IU VE/kg diet significantly increased the CQ10
concentration in the mitochondria of liver (Fig. 1A
) and
spleen (Fig. 1B
), whereas supplementing 1310 IU
VE/kg diet had an opposite effect. CQ10 and VE supplementation and tissue levels of CQ9.
The CQ9 concentrations were significantly higher in the livers of rats
fed the CQ10-supplemented diet at 14 d, and in the spleen of rats
at 14 and 28 d (Table 2
). On the other hand, CQ10 supplementation resulted in significantly
lower CQ9 values in muscle (Table 2)
. CQ10 supplementation did not
significantly alter the levels of CQ9 in the serum, heart, kidney and
brain (Table 2)
. Except in liver, dietary VE had no significant effect
on the levels of CQ9 in any tissues analyzed (Table 2)
. Higher CQ9
concentrations were found in the liver of VE-supplemented rats at
14 d, but not 28 d.
|
Rats fed the CQ10-supplemented diets had significantly higher hepatic
VE levels in both the homogenate (Fig. 2A
) and mitochondria (Fig. 3
). CQ10 supplementation had no significant effect on the concentration
of VE in the spleen (Fig. 2B
), serum (Fig. 2C
),
heart (Fig. 2D
), kidney (Fig. 4A
), skeletal muscle (Fig. 4B
) or brain (Fig. 4C
).
|
|
|
), spleen (Fig. 2B
), serum (Fig. 2C
), heart (Fig. 2D
),
kidney (Fig. 4A
), skeletal muscle (Fig. 4B
) and
brain (Fig. 4C
) of rats in a dose-dependent manner.
Similarly, VE supplementation increased VE levels in liver mitochondria
in the same fashion (Fig. 3)
. |
DISCUSSION |
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|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
,
Reahal and Wrigglesworth 1992
, Yuzuriha et al. 1983
, Zhang et al. 1995
and 1996
), we also found
significant increases in the CQ10 concentrations of serum, liver and
spleen, but not of heart, kidney, skeletal muscle and brain of
CQ10-supplemented rats. Significant increases of CQ10, however, have
been found in cerebral cortex mitochondrial concentrations of CQ10 in
12-mo-old rats after oral treatment with 200 mg CQ10/kg body mass daily
for 2 mo (Matthews et al. 1998
), and in kidney
mitochondria in 24-mo-old mice after oral CQ10 administration at a dose
of 123 mg/kg body mass daily for 13 wk (Lass et al. 1999
). It thus appears that treatment with high doses of CQ10
for longer periods may enable its uptake into other organs in addition
to liver, spleen and serum. Whether dietary VE influences tissue retention of CQ10 was examined in this study. We fed three different levels of VE along with 500 mg CQ10/kg diet and found that the rats supplemented with 100 IU VE/kg had significantly more CQ10 in both the homogenate and mitochondria of liver and spleen, whereas those supplemented with 1310 IU VE/kg had lower levels, compared with the control group not receiving VE supplementation. The mechanism of the enhancing effect of moderate levels and the suppressing effect of high levels of VE on tissue CQ10 found in our study is not yet clear. However, because both compounds are lipid soluble, it is possible that they may have a similar absorption/transport mechanism. A moderate increase in the dose of VE may elevate CQ absorption and/or incorporation, whereas high levels of VE may compete with CQ10 and thus suppress its absorption, transport and/or uptake.
CQ is synthesized in all the cells via the mevalonate pathway
(Ernster and Dallner 1995
, Maltese and Aprille 1985
), and the predominant CQ homologue in rodents is CQ9. In
this study, we examined the effect of dietary CQ10 and VE on endogenous
CQ 9 and found that CQ9 levels were altered significantly in the liver,
spleen and skeletal muscle of rats supplemented with CQ10. The findings
that CQ10 administration resulted in higher CQ9 in the liver and
spleen, the only organs that also showed an increase in CQ10, suggests
that CQ10 may spare the loss (utilization) of CQ9, or that CQ10 may
serve as a precursor of CQ9 in rats.
-Tocopherol may react with superoxide and peroxyl radicals to form
-tocopheroxyl radical (Fukuzawa and Gebicki 1983
, McCay 1985
, Niki et al. 1982
and 1984
). Many studies suggest that reducing compounds such as
ascorbic acid (McCay 1985
, Niki et al. 1982
), glutathione (Chan et al. 1991
,
Niki et al. 1982
), lipoic acid (Packer et al. 1997
) and reduced CQ (ubiquinol) (Kagan et al. 1990
, Lass and Sohal 1998
Maguire et al. 1992
, Stoyanovsky et al. 1995
) may regenerate
-tocopherol from the tocopheroxyl radical, thereby sparing or
preventing its loss. The findings that rats supplemented with CQ10 had
significantly higher VE levels in both liver homogenate and
mitochondria than those not supplemented with CQ10, provide
experimental evidence for this interaction in vivo. Similar results
were obtained by Lass et al. (1999)
who reported
increased levels of VE in mice liver and skeletal muscle mitochondria
after CQ10 supplementation.
The results obtained from this study provide experimental evidence for an interaction in vivo between exogenously administered VE and CQ10 in terms of uptake and tissue retention. The evidence also points to an interaction between these two redox compounds at the endogenous level with respect to the liver and spleen. Moderate levels of VE in the diet enhanced the retention of dietary CQ10 in these organs, whereas high levels of VE had the opposite effect. These data suggest that VE is a key determinant of CQ10 status. The data obtained also suggest that CQ10 has a sparing effect on VE, possibly via the regeneration of VE from the tocopheroxyl radical. The implications of the interaction in relation to other functions of VE and CQ10 must be examined further.
|
FOOTNOTES |
|---|
Manuscript received December 28, 1999. Initial review completed February 11, 2000. Revision accepted April 11, 2000.
|
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