Effects of L-carnitine on erythrocyte acyl-CoA, free CoA, and
glycerophospholipid acyltransferase in uremia1–3
Belén de los Reyes, José A Navarro, Rafael Pérez-García, Antonio Liras, Yolanda Campos, Belén Bornstein,
and Joaquín Arenas
ABSTRACT We studied the effects of L-carnitine treatment
in the acyl flux of erythrocyte membranes from uremic patients.
We found a significantly lower relative proportion of long-chain
acyl-CoA (LCCoA) to free CoA (FCoA) in patients than in con-
trol subjects. In addition, patients had reduced activities of both
carnitine palmitoyltransferase (CPT) and glycerophospholipid
acyltransferase (LAT; CoA dependent), and increased ratios of
long-chain acylcarnitine (LCAC) to free carnitine in their ery-
throcytes. These data support the hypothesis that acyl-trafficking
is altered in erythrocytes in uremia. After treatment with L-
carnitine, we observed a significant increase in CPT and LAT
activities as well as in the LCCoA-FCoA ratio, and a significant
decrease in the ratio of LCAC to free carnitine. These results
support the conclusion that L -carnitine supplementation
improves erythrocyte flux in uremic patients. Am J Clin Nutr
1998;67:386–90.
KEY WORDS Uremia, L-carnitine, carnitine palmitoyl-
transferase, erythrocyte, coenzyme A, CoA, membrane phospho-
lipid turnover, glycerophospholipid acyltransferase (CoA depen-
dent), end-stage renal disease, adults
INTRODUCTION
Peroxidation of polyunsaturated fatty acids esterified in ery-
throcyte membrane phospholipid is followed by increased phos-
pholipid fatty acid turnover (1), in which erythrocyte carnitine
palmitoyltransferase (CPT) has a key role (2). The reversible
transfer of long-chain fatty acids from CoA to L-carnitine, cat-
alyzed by erythrocyte CPT, modulates the ratio of acyl-CoA to
free CoA (FCoA), which is critical for the regulation of mem-
brane phospholipid fatty acid turnover (2–4). Long-chain acyl-
carnitines (LCACs) serve as a reservoir of acyl moieties for the
reacylation of membrane phospholipids, a process catalyzed by
glycerophospholipid acyltransferase (LAT; CoA dependent; EC
2.3.1.48) (2, 3).
Blood carnitine is partitioned into a plasma carnitine com-
partment and an erythrocyte carnitine compartment (5). Human
erythrocytes contain significant concentrations of L-carnitine and
its esters (5–7). Because erythrocyte carnitines do not freely
exchange with plasma, they may have been acquired when the
cells were erythrocyte precursors and have remained as the cells
matured (6). Erythrocyte carnitine concentrations are the sum of
free carnitine, short-chain acylcarnitine, and LCAC concentra-
tions. LCACs seem to regulate the activities of some enzymes of
human erythrocyte membranes as well as some of their molecu-
386 Am J Clin Nutr 1998;67:386–90. Printed in USA. © 1998 American Society for Clinical Nutrition
lar properties, such as stability and rigidity (8).
We previously documented an alteration in both CPT activi-
ties and the ratio of LCAC to free carnitine in erythrocytes from
uremic patients (9). We now provide direct evidence of both
alteration in LAT activity and abnormal ratios of long-chain
acyl-CoA (LCCoA) to FCoA. In addition, we report the effects
of L-carnitine supplementation on CPT activity, LAT activity,
CoA concentration, and carnitine concentration in erythrocytes
from uremic patients.
SUBJECTS AND METHODS
Patients
Thirty-six patients, 20 men and 16 women, with end-stage
renal disease of varying etiologies were studied. Their ages
ranged from 40 to 72 y (x– ± SD: 55 ± 11.4 y), and they had
undergone regular hemodialysis treatment for between 11 and 67
mo (36.7 ± 12.5 mo). Informed consent was obtained from all
patients. They had normal blood pressures while taking antihy-
pertensive medication, and were stable and ambulatory with no
intercurrent diseases. All patients had been receiving erythropoi-
etin treatment for ≥ 9 mo, had a hematocrit value between 0.30
and 0.35, and normal iron status. Plasma concentrations of both
folic acid and vitamin B-12 were within the normal range. Of the
36 patients studied, 15 (group B) had received 3–5 mg L-
carnitine/kg body wt intravenously at the end of each dialysis
session during the 6 mo before the beginning of the study. Dur-
ing the study, patients were advised not to change their dietary
habits. Current medication, which consisted mainly of antihy-
pertensive drugs, was also not changed. Hemodialysis was done
three times weekly for 3.5–5 h with a dialysis bath containing
1
From the Centro de Investigación, Hospital 12 de Octubre; the Servicio
de Nefrología, Hospital Gregorio Marañón; the Departamento de Bioquímica
y Biología Molecular, Facultad de Ciencias, Universidad Autónoma de
Madrid; and the Servicio de Bioquímica, Hospital Severo Ochoa, Leganés,
Madrid.
2
Supported by grant 95/0658 from Fondo de Investigación Sanitaria
(FIS), Ministry of Health, Spain; by Sigma-Tau, Spain; and by grant 96/5567
from FIS (to JAN).
3
Address reprint requests to J Arenas, Centro de Investigación, Hospital
12 de Octubre, Carretera de Andalucía Km 5.4. 28041 Madrid, Spain. E-mail:
jarenas@h12o.es.
Received February 28, 1997.
Accepted for publication October 15, 1997.
 REYES ET AL
bicarbonate. The control group consisted of 30 normotensive
individuals (17 men and 13 women) with no medical problems
whose ages ranged from 42 to 70 y (56 ± 10.7 y). The study pro-
tocol was approved by the local Human Subjects Committee.
Study design
Twenty-one patients (group A) were studied to evaluate the
influence of uremia on erythrocyte CPT activity and erythrocyte
FCoA, LCCoA, free carnitine, and LCAC concentrations. In this
group we also studied the effects of L-carnitine therapy on such
variables. An additional group of 15 patients receiving L-carnitine
regularly (group B) was studied to assess the effects of discontin-
uation of the therapy. LAT activity was measured in 8 of the 21
patients in group A but was not evaluated in group B patients.
Group A
At day 0 of the study, 10–15 mL blood was drawn and col-
lected into heparin- or EDTA-treated tubes to make baseline
measurements. Blood samples were obtained before dialysis in
the morning and after fasting. Immediately postdialysis on day 0,
these patients were treated intravenously with 3–5 mg L-carni-
tine/kg body wt (CARNICOR; Sigma-Tau, Alcalá de Henares,
Spain) after every dialysis session. L-Carnitine supplementation
was continued for 90 d. Blood samples were taken again at days
30 and 90 and the indexes were reevaluated. LAT activity was
only measured before and after 1 mo of therapy.
Group B
At day 0 of the study, blood samples were taken to measure
steady state concentrations in L-carnitine–treated patients. Then,
L-carnitine therapy was discontinued and samples were taken
again 30 d after the withdrawal of L-carnitine. All blood samples
were obtained before dialysis in the morning and after fasting.
Blood samples from the control group (n = 30) were also drawn
in the morning after fasting.
Methods
Materials
L-Methyl-[3H]carnitine hydrochloride (2.22 TBq/mmol, or 60
Ci/mmol) was obtained from Amersham Iberica (Madrid), 1-
[14C]acetyl-CoA (14.8 MBq/mmol, or 40 mCi/mmol) and 1-
[14C]palmitoyl-CoA (7.4 MBq/mmol, or 0.5 mCi/mmol) were
from ICN Radiochemical (Irvine, CA). Thin-layer chromatogra-
phy plates and Whatman LK6 silica gel were from Carlo Erba
(Milan, Italy). All other compounds used were reagent grade.
Preparation of washed erythrocytes and ghosts
Venous blood was collected before each hemodialysis session
in heparin or EDTA, and leukocytes and platelets were removed
by passage through a column of a-cellulose and microcrystalline
cellulose (10). Erythrocytes were then washed three times with
cold 0.9% NaCl. Membrane ghosts were prepared from washed
cells in heparin, which were lysed in 30 volumes of cold lysing
buffer (5 mmol NaH2P04/L, 0.1 mmol phenylmethane sulfonyl
fluoride/L, pH 7.4). The lysed cells were then centrifuged for 10
min at 30 3 g at 4 °C and the resulting pelleted ghosts were
washed four times (11). The ghosts were collected in 5 mmol
NaH2P04/L, pH 7.4. Protein concentration was determined
according to Bradford (12).
387
CPT assay
CPT activity was measured in ghost erythrocytes by a radio-
chemical procedure (13) in 220 mmol sucrose/L, 40 mmol
KCl/L, 10 mmol tris-HCl/L, and 1 mmol/L ethyleneglycote-
traacetic acid (pH 7.4 at 30 °C), except that the final concentra-
tion of palmitoyl-CoA was 50 µmol/L, with 1.3 g bovine serum
albumin/L; L-[3 H]carnitine was 1 mmol/L and the time of incu-
bation was 30 min.
Free carnitine, LCAC, FCoA, and LCCoA determinations
Free carnitine and LCAC concentrations were measured by an
optimized radiochemical enzymatic assay (14) in washed ery-
throcytes collected in EDTA. FCoA and LCCoA concentrations
were measured as described previously (15) in washed erythro-
cytes collected in EDTA.
LAT assay
LAT activities were determined as described previously (2).
The reaction mixture contained 50 mmol tris-HCl/L, pH 7.5,
with 0.5% bovine serum albumin, 5 mmol MgCl 2/L, 0.5 mmol
ATP/L, 1 mmol dithiothreitol/L, 100 mmol 1-[ 14C]palmitoyl-
CoA/L (7.4 MBq/mol, or 0.5 Ci/mol), and 150 mmol lysophos-
phatidylcholine/L.
Cytochrome-c oxidase activity
The activity was determined in ghost erythrocytes by moni-
toring the decrease in absorbance at 550 nm reduced cytochrome
c (9). Reduced cytochrome c was prepared fresh before each
experiment by adding a few grains of sodium borohydride to a
1% solution in 10 mmol K2HPO4/L buffer (pH 7.0).
Statistical analysis
Data are given as means ± SDs unless otherwise indicated.
Results were analyzed by using the statistical package R-SIGMA
(Horus-Hardware, Madrid). Unpaired t test, paired t test, and
one-factor repeated-measures analysis of variance (ANOVA)
were used to estimate statistical significance. Significance was
set at P < 0.05.
RESULTS
Cytochrome-c oxidase activity in erythrocytes
To evaluate the contribution of mitochondrial CPT from con-
taminating reticulocytes to the total CPT activity in erythrocyte
membrane, we measured the activity of cytochrome-c oxidase, a
mitochondrial membrane marker, in membrane preparations
from patients (n = 6) and control subjects (n = 5) . Activities of
cytochrome-c oxidase were very low in both patients and control
subjects (0.57 ± 0.05 and 0.55 ± 0.08 nmol · min21 · mg
protein21, respectively), indicating lack of contamination with
mitochondria from reticulocytes. Therefore, the activity of CPT
measured in membrane preparations was contributed almost
entirely by erythrocyte membranes.
Erythrocyte CoA and carnitine concentrations, and LAT
and CPT activities in uremic patients
Basal values for erythrocyte CPT, carnitine, and CoA for group
A are shown in Table 1. Values for erythrocyte CPT, LCCoA, and
LCCoA:FCoA in uremic patients were significantly lower than in
control subjects. Concentrations of erythrocyte, free carnitine,
388 L-CARNITINE AND UREMIA

TABLE 1
Free carnitine, LCAC, LCAC:free carnitine, CPT, FCoA, LCCoA, and LCCoA:FCoA in erythrocytes from control subjects and uremic patients in group A1

Uremic patients given carnitine

Control subjects Basal 1 mo 3 mo
(n = 30) (n = 21) (n = 21) (n = 21)
FCoA 2.5 ± 0.70 3.7 ± 1.02 2.7 ± 0.84 2.6 ± 0.84
(nmol/g hemoglobin)
LCCoA 0.38 ± 0.12 0.28 ± 0.082 0.40 ± 0.124 0.41 ± 0.114
(nmol/g hemoglobin)
LCCoA:FCo 0.15 ± 0.006 0.08 ± 0.0032 0.14 ± 0.0074 0.16 ± 0.0074
Free carnitine 59.2 ± 21.5 104.2 ± 31.92 203.38 ± 79.604 219.8 ± 86.74
(nmol/g hemoglobin)
LCAC 8.5 ± 2.9 20.1 ± 8.42 25.1 ± 8.35 29.5 ± 10.04
(nmol/g hemoglobin)
LCAC:free carnitine 0.15 ± 0.03 0.21 ± 0.0073 0.13 ± 0.064 0.14 ± 0.064
CPT 0.42 ± 0.14 0.32 ± 0.173 0.67 ± 0.184 0.67± 0.244
(nmol · min21 · mg protein21)
1–
x ± SD. LCAC, long-chain acylcarnitine; CPT, carnitine palmitoyltransferase; FCoA, free coenzyme A; LCCoA, long-chain acyl coenzyme A.
2,3
Significantly different from control subjects (unpaired t test): 2 P < 0.001, 3 P < 0.05.
4,5
Significant differences among basal 1-mo, and 3-mo values (repeated-measures one-factor ANOVA): 4 P < 0.01, 5 P < 0.05.

LCAC, the ratio of LCAC to free carnitine, and FCoA were all
significantly higher in patients than in control subjects. Activities
of LAT in patients (n = 8) were significantly lower than in control
subjects (n = 7) (1.8 ± 0.8 and 3.9 ± 1.0 nmol · min21 · mg protein
21
, respectively; P < 0.01, unpaired t test).
Effects of L-carnitine supplementation
Table 1 also lists erythrocyte CPT activity and concentrations of
erythrocyte carnitine and CoA after L-carnitine treatment in group
A. After 1 mo of supplementation with L-carnitine, the activity of
erythrocyte CPT and concentrations of erythrocyte free carnitine,
LCCoA, and the LCCoA-FCoA ratio increased significantly;
LCAC concentrations increased significantly after 3 mo of ther-
apy. The relative proportion of erythrocyte LCAC to free carnitine
was significantly reduced with L -carnitine. After
1 mo of L-carnitine treatment, LAT values increased up to con-
centrations similar to those of control subjects (1.8 ± 0.8 nmol ·
min21 · mg protein21 before therapy compared with 3.7 ± 1.3 nmol
· min21 · mg protein21 after therapy; n = 8; P < 0.01, paired t test).
Effects of L-carnitine withdrawal
The activity of erythrocyte CPT and concentrations of ery-
throcyte carnitine and CoA before and after cessation of L-carni-
tine therapy in group B are shown in Table 2. After 1 mo of
L-carnitine withdrawal, concentrations of erythrocyte free carni-
tine, LCAC, LCCoA, and the LCCoA-FCoA ratio decreased sig-
nificantly to values similar to those at baseline in group A. Ery-
throcyte CPT activities were also significantly reduced, but the
values were slightly above those at baseline in group A. Values
for FCoA increased significantly with L-carnitine withdrawal.
The ratio of LCAC to free carnitine increased, although not sig-
nificantly.
DISCUSSION
Erythrocyte membrane lipid peroxidation is a common feature
in uremia (1, 16). This event is commonly followed by increased
membrane phospholipid fatty acid turnover, which depends on
the activities of both LCCoA synthetase and LAT (2, 3). The for-
mer generates acyl-CoA from fatty acids and CoA, whereas the
latter reacylates lysophospholipids by using acyl-CoA as sub-
strate. When the rate of formation of acyl-CoA becomes differ-
ent from that of its utilization for reacylation, the acyl-CoA pool
and the acylCoA-FCoA ratio become altered, leading to distur-
bances in erythrocyte phospholipid fatty acid turnover (2).
Arduini et al (2) showed that CPT can be considered an integral
component of the pathway for membrane phospholipid acid
turnover in human erythrocytes. Erythrocyte CPT maintains a
favorable ratio of acyl-CoA to FCoA by forming acylcarnitine
from free carnitine and acyl-CoA (2). Given the sensitivity of
CPT to the mass action ratio of the substrates, any variation of
the ratio of acyl-CoA to FCoA can be compensated for by this
enzyme. In erythrocytes, the CPT action would be twofold: pro-
vide acyl units at no ATP cost and buffer the harmful elevation of
FCoA, which is an inhibitor of the enzyme LAT (4). Consistent
with our previous report (9), we found reduced CPT activity in
erythrocytes from uremic patients. The decrease in erythrocyte
CPT activity may cause consequences similar to those observed
after CPT inhibition (2), in which the lack of buffering activity
of CPT alters the ratio of acyl-CoA to FCoA, and eventually the
availability of fatty acid moieties for reacylation. In this biolog-
ical model, the inhibition of CPT caused a depression of the rea-
cylating capability of complex membrane lipids. More impor-
tantly, we found a marked decrease in both LAT activity and the
LCCoA-FCoA ratio in uremic patients, which strongly supports
an alteration in acyl trafficking in their erythrocytes. Consistent
with previous data (4), the relatively high concentrations of
FCoA observed may account for the inhibition of the reacylating
enzyme LAT.
It has been argued that erythrocytes do not contain carnitine or
carnitine esters (17, 18). Some authors (19) documented that the
use of tris buffer could interfere with the carnitine assay by act-
ing as acetyl receptors for carnitine acetyltransferase. Our
results, determined with a modified radiochemical-enzymatic
 REYES ET AL
TABLE 2
LCCoA, FCoA, LCCoA:FCoA, free carnitine, LCAC, LCAC:free carni-
tine, and CPT in erythrocytes from uremic patients in group B1
L-Carnitine L-Carnitine
for 6 mo withdrawn for 30 d
(n = 15) (n = 15)
LCCoA 0.43 ± 0.12 0.30 ± 0.102
(nmol/g hemoglobin)
FCoA 2.5 ± 0.70 3.5 ± 1.12
(nmol/g hemoglobin)
LCCoA:FCoA 0.17 ± 0.008 0.09 ± 0.004
(nmol/g hemoglobin)
Free carnitine 270.1 ± 102.9 132.0 ± 58.72
(nmol/g hemoglobin)
LCAC 29.0 ± 10.2 18.2 ± 3.32
(nmol/g hemoglobin)
LCAC:free carnitine 0.11 ± 0.04 0.17 ± 0.11
CPT 0.58 ± 0.18 0.42 ± 0.192
(nmol · min21 · mg protein21)
1–
x ± SD. LCAC, long-chain acylcarnitine; CPT, carnitine palmitoyl-
transferase; FCoA, free coenzyme A; LCCoA, long-chain acyl coenzyme
A.
2
Significantly different from L-carnitine for 6 mo, P < 0.01 (paired t
test).
assay, show concentrations of erythrocyte carnitines in control
subjects similar to those documented previously (6, 7). Cooper et
al (6) showed clearly that the presence of carnitine in erythro-
cytes is not the result of leukocyte contamination. In uremic
patients, erythrocyte carnitine values were similar to those
reported by Wanner et al (7). Further evidence of alteration of the
erythrocyte ratio of acyl-CoA to FCoA in uremic patients comes
from erythrocyte carnitine concentrations. The ratio of LCAC to
free carnitine represents a reliable index of the ratio of acyl-CoA
to CoA (2). The LCAC pool is an important reservoir of acyl
units, which are actively utilized when erythrocytes have meta-
bolic requirements (2). Patients had greater ratios of LCAC to
free carnitine than did control subjects, thus indicating that there
is a relative shortage of free carnitine and a lack of equilibrium
between the acyl-CoA and FCoA pools in erythrocytes in ure-
mia. Erythrocyte CPT is known to have a freely reversible flux,
the direction of which relies on the mass action ratio of the sub-
strates (2). Because of the high concentrations of free carnitine
in erythrocytes of uremic patients, the equilibrium of residual
CPT would shift toward acylcarnitine rather than toward acyl-
CoA. The observation that the ratio of LCCoA to FCoA
decreases and, concurrently, that of LCAC to free carnitine
increases, strongly suggests this possibility. High concentrations
of LCAC are known to inhibit erythrocyte Na +/K+ transporting
ATPase (20). In addition, molecular dynamics of human erythro-
cyte membrane (21), its stability, as well as its rigidity (8), seem
to depend on erythrocyte LCAC concentrations and on the ratio
of LCAC to free carnitine. Taken together, all these data support
the assumption that alterations in the ratio of LCCoA to FCoA or
of LCAC to free carnitine may also contribute per se to dysfunc-
tion of erythrocyte membranes in uremic patients.
Our data indicate that L-carnitine therapy induces a rise in the
activity of both LAT and CPT and restores the equilibrium
between LCCoA and FCoA. Although erythrocyte LCAC and
free carnitine concentrations after L-carnitine therapy went in
389
opposite directions from those of control subjects, the ratio of
LCAC to free carnitine decreased to normal values. This
decrease in the ratio with carnitine supplementation was largely
due to a very large further increase in free carnitine and a lesser
increase in LCAC. In addition, withdrawal of L-carnitine caused
opposite effects, which reinforces our observations. However, it
is very difficult to figure out how carnitine supplementation
works in cells in which there is plenty of FCoA and plenty of
free carnitine. We suggest that greater availability of carnitine
may unblock the inhibition of CPT activity, and this in turn may
lead to favorable ratios of LCCoA to FCoA and of LCAC to free
carnitine. These findings strongly support the hypothesis that
withdrawal of L-carnitine therapy contributes to maintaining nor-
mal acyl trafficking in erythrocyte membrane phospholipids in
uremic patients. Because erythrocyte carnitine does not freely
exchange with plasma (6), carnitine uptake by erythrocyte pre-
cursors within bone marrow may account for the effects found in
mature erythrocytes.
As suggested previously by Arduini et al (22), L-carnitine and
its acyl esters should be considered as part of the defensive bio-
chemical network devoted to protection against free radical tox-
icity. This network is formed by a primary defense barrier that
prevents oxidative injury by scavenging the initiating species and
terminating the radical propagation reactions, and a secondary
defense system that eventually repairs the damage that occurs
after the oxidative attack. Several reports show that carnitine
protects the heart against ischemia-reperfusion injury (23, 24).
More importantly, our data reveal that L-carnitine belongs to the
secondary antioxidant repair system. In fact, L-carnitine induces
the activity of both CPT and LAT in erythrocytes, which modu-
late the acyl flux in erythrocyte membranes, restoring a favorable
LCCoA-FCoA ratio. This mechanism would favor the removal
and replacement of those molecules that have been oxidatively
modified, thus allowing recovery of proper cellular integrity.
Our data provide a rationale for the use of L-carnitine supple-
mentation in hemodialysis patients to reduce erythropoietin
requirements (25, 26). These data may help explain the longer
life span of erythrocytes observed in uremic patients treated with
L-carnitine (26).
We are indebted to Juan Antonio Ayala for providing samples from
patients and to Peggy Borum for her helpful criticism and for reviewing the
manuscript.
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