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PubMed1996

Effect of carnitine administration on glycine metabolism in patients with isovaleric acidemia: significance of acetylcarnitine determination to estimate the proper carnitine dose.

In isovaleric acidemia (IVA), accumulated isovaleryl-CoA in the mitochondrion induces variable metabolic disturbances. To remove intramitochondrial isovaleryl groups, glycine therapy has been advocated primarily. On the other hand, secondary carnitine deficiency has been documented in this disorder and carnitine supplementation alone has been reported to be effective. In the present study, we administered carnitine and glycine to patients with IVA, and investigated serum carnitine and urinary excretion of total and free carnitine, acylcarnitine profile (i.e., isovalerylcarnitine and acetylcarnitine), and isovalerylglycine. By adding carnitine to glycine supplementation, more isovalerylglycine, not only isovalerylcarnitine, was excreted in the urine. Acetylcarnitine was detected in the urine only when sufficient carnitine was supplemented. We concluded that combined therapy of glycine and carnitine is more effective and safer to eliminate isovaleryl-CoA in IVA than conventional therapy using either glycine or carnitine. Urinary acetylcarnitine concentration might be a good marker indicating the optimal dose of L-carnitine supplementation.

Acetylcarnitine↗
PubMed1976

Effects of carnitine administration, fasting, and exercise on urinary carnitine excretion in man.

1. In this study, the carnitine level in 24-hr urine has been determined in males, (a) before and after a single dose of 500 mg (as carnitine) of DL-carnitine chloride, (b) during fasting, and (c) before and after a severe running program (3 x 2,000 m/8-8.5 min). 2. After the administration of DL-carnitine chloride, the urinary carnitine excretion was increased by only approximately 10% of the dose, suggesting a large body pool size of carnitine. 3. Urinary carnitine excretion was significantly increased during five-day fasting; a maximum level of 2.17 +/- 0.24 (mean and SD) mmoles/day was 4.6 times higher than the usual level of 0.47 +/- 0.10 mmoles/day (p less than 0.001). Respiratory quotients (RQ) decreased significantly (p less than 0.01) from the control value of 0.81 +/- 0.03 to the value of 0.75 +/- .02 after five-day fasting and was significantly correlated with urinary carnitine levels (r = 0.62, p less than 0.05). 4. The urinary excretion of carnitine increased slightly with heavy running exercise. 5. The results are discussed in relation to the physiologic regulation of the rate of carnitine synthesis.

Adult↗
PubMed1982

Carnitine and carnitine palmitoyltransferase in fatty acid oxidation and ketosis.

Carnitine is an essential factor in long-chain fatty acid oxidation. Carnitine acts as a carrier of fatty acyl groups from the cytoplasm to the mitochondrion. Long-chain acyl-CoA derivatives do not penetrate the mitochondrial inner membrane. Carnitine palmitoyltransferase A (CPT-A), located on the external surface of the inner membrane, catalyzes the conversion of cytoplasmic long-chain acyl-CoA and carnitine into acylcarnitine. The acylcarnitine is reconverted to intramitochondrial acyl-CoA by the action of carnitine palmitoyltransferase B located in the inner membrane. Now, the acyl-CoA is available for beta-oxidation in the matrix. An inner membrane carnitine-acylcarnitine translocase exchanges carnitine and acylcarnitine across the inner membrane but its role is long-chain acyl transfer has not been established. The tissue concentration of carnitine is important; liver carnitine is correlated with the rate of hepatic ketoacid production. In liver, malonyl-CoA, an intermediate in fatty acid synthesis, is proposed to regulate the activity of CPT-A. Studies using various purified transferases have not provided an answer to the question of whether the two activities expressed in mitochondria are separate enzymes. The absence of only CPT-A activity in isolated skeletal muscle mitochondria obtained from a patient with a lipid-storage myopathy suggests two separate activities.

Acidosis↗
PubMed1983

Tissue carnitine concentrations after total parenteral nutrition with and without L-carnitine supplementation.

The concentrations (mumoles/g dry weight) of total carnitine (TC), free carnitine (FC) and acylcarnitine (AC) were determined in skeletal muscle, heart, liver, kidney and brain cortex of male mini pigs (4000-5000 g) after seven days of total parenteral nutrition (TPN) with amino acids 5% (3.0g/kg/d), glucose (25g/kg/d) and lipids 20% (4g/kg/d). This regime was administered with L-carnitine supplementation (1.5 mg/kg/d; n = 7) (group 1) and without it (n = 5) (group 2). Orally alimented animals (n = 5) served as controls (group 3). (Average carnitine intake: 3 mg/d) Carnitine free TPN affected only the concentrations in muscle. TC was markedly reduced (3.6 +/- 0.8) when compared with oral controls (5.8 +/- 0.7) (p<0.01). This decrease was exclusively due to AC, whereas FC concentrations remained almost unchanged. In group 1 the concentrations of TC in skeletal muscle, heart and brain cortex were higher than in both the other groups. The increase was mainly due to AC and FC remained unchanged in heart and brain. The concentrations in liver and kidney were not affected by either carnitine free or carnitine supplemented TPN. AC, determined as described, consists almost entirely of acid soluble acetyl-carnitine, the major product of fatty acid oxidation. Since the AC concentrations were almost exclusively altered by the two TPN-regimes we conclude that the observed changes reflect regulatory changes of fatty acid oxidation. Thus the decrease of muscle TC in group 2 is considered a consequence of an insulin induced down regulation (plasma insulin: mean 20 muU/ml; maximum: 60 muU/ml) of fatty acid oxidation in consequence of high glucose intake (25 g/kg/d). The increased TC concentrations after carnitine supplemented TPN are discussed to reflect an enhancement of oxidative degradation of fatty acids as a pharmacological effect of L-carnitine.

Journal Article↗
PubMed1999

Cefetamet pivoxil treatment causes loss of carnitine reserves that can be prevented by exogenous carnitine administration.

Two groups of pediatric patients receiving cefetamet pivoxil treatment (3 x 500 mg daily) for 7 days were studied. In the first group (Group A) the drug was administered alone; in the second group (Group B) the drug was given in combination with a molar excess of carnitine (3 x 1 g). Medication with cefetamet pivoxil alone was associated with a large urinary excretion of pivaloylcarnitine: Approximately 71% of the daily pivalate intake could be eliminated as carnitine ester in the urine. In this group, the plasma level and the urinary output of free carnitine decreased. By contrast, in Group B, the administration of molar excess of carnitine aided stochiometric elimination of pivalate as carnitine ester, and the plasma levels and carnitine-free urinary output were unchanged. The data show that medication of cefetamet pivoxil results in the formation of pivaloylcarnitine in children; the sustained loss of carnitine esters can ultimately lead to carnitine deficiency. Molar excess of exogenous carnitine aids in the elimination of pivalate derived from cefetamet pivoxil therapy and helps to maintain the carnitine reserves.

Journal Article↗
PubMed1991

Carnitine acyltransferases in normal human skeletal muscle and in muscle of patients with carnitine palmitoyltransferase deficiency.

Carnitine acyltransferase activities were studied in normal human skeletal muscle and in muscle of three patients with carnitine palmitoyltransferase deficiency. Carnitine acetyltransferase (CAT), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase (CPT) were differentiated (i) by the use of the substrates acetyl-CoA, octanoyl-CoA, lauroyl-CoA, and palmitoyl-CoA, (ii) by the inhibitors malonyl-CoA, chlorpromazine, and dithio-bis-nitrobenzoic acid (DTNB), and (iii) by the solubilities of the carnitine acyltransferase activities after centrifugation at 48,000 g for 30 min. The results are consistent with the notion of three different carnitine acyltransferases in human skeletal muscle: a membrane-bound malonyl-CoA-sensitive CPT, a soluble malonyl-CoA-insensitive CAT, and a malonyl-CoA-sensitive COT that is not attached to the mitochondrial membrane. The different solubilities of the carnitine acyltransferases allow a clear differentiation of CPT from CAT and COT in homogenates of previously frozen muscle biopsies whereas a separate determination of CAT and COT is only partially possible. In patients with CPT deficiency total CPT activity was within the normal range but was abnormally inhibited by malonyl-CoA and chlorpromazine. Activities of carnitine acyltransferases with the substrates acetyl-CoA and octanoyl-CoA were normal indicating that the biochemical defect in CPT deficiency is confined to CPT without compensatory changes of CAT and COT.

Carnitine Acyltransferases↗
PubMed1985

Inhibition of acetyl-carnitine oxidation in rat brown-adipose-tissue mitochondria by erucoyl-carnitine is due to sequestration of CoA.

The cause underlying the inhibitory effect of erucoyl-carnitine on acetyl-carnitine oxidation in rat brown-adipose-tissue mitochondria was investigated. The inhibition was shown to be of a noncompetitive nature, with an I50 of about 10 microM erucoyl-carnitine. Erucoyl-carnitine did not inhibit the respiratory chain or the citric acid cycle to a significant degree. Incubation of mitochondria with erucoyl-carnitine led to about 2/3 of all CoA being sequestered in the form of acid-insoluble esters (probably erucoyl-CoA). This sequestration had an apparent Km of about 10 microM. Erucoyl-carnitine also inhibited pyruvate oxidation with an I50 of about 10 microM. When added at this concentration, it also inhibited the oxidation of a wide variety of acyl-carnitines by about 50%, despite very different oxidation rates of these different acyl-carnitines. It was concluded that the inhibitory effect of erucoyl-carnitine on all CoA-dependent substrates could be adequately explained by the suggestion that erucoyl sequesters a significant fraction of mitochondrial matrix CoA as slowly metabolizable erucoyl-CoA esters. Possible physiological effects of this sequestration for brown adipose tissue thermogenesis are discussed.

Acetylcarnitine↗
PubMed1995

Carnitine-acylcarnitine translocase activity in cardiac mitochondria from aged rats: the effect of acetyl-L-carnitine.

Age-related changes in mitochondrial fatty acids metabolism may underlie the progressive decline in cardiac function. The effect of aging and acute treatment with acetyl-L-carnitine on fatty acids oxidation and on carnitine-acylcarnitine translocase activity in rat heart mitochondria was studied. Rates of palmitoylcarnitine supported respiration as well as carnitine-carnitine and carnitine-palmitoylcarnitine exchange reactions were all depressed (approx. 35%) in heart mitochondria from aged rats. These effects were almost completely reversed following treatment of aged rats with acetyl-L-carnitine. Heart mitochondrial cardiolipin content was significantly reduced (approx. 38%) in aged rats. Treatment of aged rats with acetyl-L-carnitine restored the level of cardiolipin to that of young rats. It is suggested that acetyl-L-carnitine is able to reverse age-related decrement in mitochondrial carnitine-acylcarnitine exchange activity by restoring the normal cardiolipin content.

Acetylcarnitine↗
PubMed1990

Carnitine transport and tissue carnitine accretion in rats.

In rats, circulating carnitine levels were highly correlated with skeletal muscle and heart carnitine concentrations over the range of 26-69 microM serum carnitine, but not at higher extracellular carnitine concentrations (70-188 microM). By contrast, circulating carnitine levels over the entire range studied (26-188 microM) correlated with liver and kidney carnitine concentrations. For each tissue the range of extracellular carnitine concentrations which correlated with the tissue carnitine concentration corresponded with the linear or nearly linear portion of the Michaelis-Menten curve for transport of carnitine in vitro.

Animals↗
PubMed1996

Isovaleric acidemia: response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy.

OBJECTIVE: To assess the effectiveness of glycine and carnitine therapy on isovaleryl conjugate excretion in isovaleric acidemia (IVA). STUDY DESIGN: Urinary isovalerylglycine (IVG) and isovalerylcarnitine (IVC) were measured from 12-hour urine specimens collected overnight from an 8-year-old patient with IVA (who had no residual activity of isovaleryl-CoA dehydrogenase in fibroblasts) before and during 3-week courses of supplementation with glycine alone (250 mg/kg per day), L-carnitine alone (100 mg/kg per day) therapy, and both of these agents combined, with a 2 gm leucine challenge performed at the end of each treatment period. RESULTS: Isovalerylglycine was the predominant metabolite excreted throughout the study, and its mean value doubled with glycine treatment. Isovalerylcarnitine excretion was minimal without carnitine supplementation. L-Carnitine therapy was associated with a 50% decline in excretion of IVG without a fully compensatory increase in IVC. The readdition of glycine to the carnitine regimen resulted in an increase in IVG excretion. Leucine challenge resulted in a 2.7- and 2.4-fold increase of IVG and IVC excretion, respectively, during L-carnitine therapy but not during glycine supplementation, and a 3.5- and 4-fold increase in excretion of both metabolites during glycine plus L-carnitine therapy. Total conjugate excretion was highest after a leucine load during combined glycine and L-carnitine therapy. CONCLUSIONS: Combined glycine and L-carnitine therapy maximally increases isovaleryl conjugate excretion during metabolic stress but not under stable conditions.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Characterization of the endogenous carnitine transport and expression of a rat renal Na(+)-dependent carnitine transport system in Xenopus laevis oocytes.

L-Carnitine transport was characterized in Xenopus laevis oocytes before and after injection of mRNA isolated from rat renal cortex. Non-injected oocytes revealed endogenous Na(+)-dependent transport of L-carnitine. After injection of 15 ng of rat kidney mRNA, the Na(+)-dependent L-carnitine transport increased 2-3-fold, reaching maximal activity after 5-6 days. The expressed carnitine transport was maximal at pH 7.5, whereas the endogenous transport showed no clear maximum between pH 6.0 and 8.5. Kinetic analysis revealed apparent Km values for L-carnitine of 66 microM for the endogenous and 149 microM for the expressed transport. Trimethyl-lysine and D-carnitine inhibited both the endogenous and the expressed transport. In contrast, L-acetylcarnitine, L-isovalerylcarnitine, L-palmitoylcarnitine and butyrobetaine inhibited predominantly the expressed transport, whereas glycinebetaine had no inhibitory effect on either transport system. Size-fractionated rat renal-cortex mRNA (median size 2 kb) induced a 3-fold higher L-carnitine transport than did unfractionated mRNA. These studies demonstrate that Xenopus laevis oocytes exhibit Na(+)-dependent L-carnitine transport and provide the basis for expression-cloning of a rat renal Na(+)-dependent L-carnitine transport system.

Animals↗
PubMed1987

Effect of diet on plasma carnitine levels and urinary carnitine excretion in humans.

This investigation determines the effect of two isocaloric diet regimens on plasma carnitine and urinary carnitine excretion in man. Seven healthy men were served a high-carbohydrate, low-fat (C) or a low-carbohydrate, high-fat (F) diet for 2 wk, ie, one diet regimen for 4 d followed by a 3-d break and concluded with 4 d more on the other diet regimen. The two regimens contained the same amount of carnitine-rich food. Plasma free carnitine rose significantly from the initial value on F diet and was significantly higher from day 3 than C diet. Plasma acyl carnitine increased on both diets. Urinary excretion of carnitine increased only on F diet. Renal clearance of both free and acyl carnitine was significantly greater on F diet than on C diet. Results showed that composition of a diet with constant carnitine content influenced carnitine metabolism in man.

Adult↗
PubMed2002

Osmoprotection by carnitine in a Listeria monocytogenes mutant lacking the OpuC transporter: evidence for a low affinity carnitine uptake system.

A deletion mutant of Listeria monocytogenes lacking OpuC, an ABC transporter responsible for the uptake of the compatible solute carnitine, was constructed and carnitine transport assays confirmed that carnitine transport was defective in this mutant. However, the mutant retained the ability to derive osmoprotection from carnitine, suggesting the presence of a second uptake system for this compatible solute. Measurement of intracellular carnitine pools during balanced growth confirmed that the opuC mutant accumulated high levels of carnitine. These pools were only achieved in the mutant when high levels (1 mM) of carnitine were present extracellularly. When a lower level (100 microM) was supplied in the medium the mutant failed to accumulate a substantial intracellular pool and failed to derive osmoprotection from carnitine. These data suggest the presence of a second low affinity carnitine uptake system in this osmotolerant pathogen.

ATP-Binding Cassette Transporters↗
PubMed1998

Effect of L-carnitine and palmitoyl-L-carnitine on erythroid colony formation in fetal mouse liver cell culture.

The administration of L-carnitine to patients undergoing hemodialysis increases hematocrit and improves the response to recombinant human erythropoietin (rhEPO). This suggests a contribution by carnitine to erythrocyte membrane function or erythropoiesis. We investigated the effect of L-carnitine and palmitoyl-L-carnitine on erythropoiesis by assessing erythroid colony formation in in vitro fetal mouse liver cell cultures. L-Carnitine or palmitoyl-L-carnitine was added with rhEPO to fetal mouse liver cell cultures. Doses of L-carnitine of up to 200 micromol/l to the culture had no effect on colony formation. In contrast, the addition of above 12.5 micromol/l palmitoyl-L-carnitine into the culture increased colony formation significantly. These results suggest that long-chain acyl carnitine may have an effect on erythropoiesis.

Animals↗
PubMed1996

Carnitine-related alterations in patients with intermittent claudication: indication for a focused carnitine therapy.

BACKGROUND: Carnitine metabolism is altered in peripheral arterial disease. L-carnitine supplementation may correct these alterations and improve walking performance. METHODS AND RESULTS: Plasma levels of carnitine and its esters were measured at rest and after maximally tolerated exercise in 22 claudicant patients and 8 normal subjects. One week later, this protocol was repeated in patients after random administration of placebo or L-carnitine (500 mg IV as a single bolus). Two groups of patients emerged. In 10 patients (group IC1), the plasma level of acetylcarnitine at rest was 3.7 +/- 0.2 micromol/L and increased significantly (P<.01) at maximally tolerated exercise. In 12 patients (group IC2), the resting level of plasma acetylcarnitine was elevated (7.9 +/- 0.7 micromol/L, P<.01) and decreased with exercise. Furthermore, group IC2 patients had a significantly lower walking capacity than group IC1 patients. In both groups, placebo did not affect the metabolic profile, nor did it improve exercise performance. Conversely, after L-carnitine administration, all but one patient in group IC2 (n=7) showed an increase in plasma acetylcarnitine concentration during exercise versus the decrease observed without L-carnitine. This metabolic effect was accompanied by a significant increase (P<.01) in walking capacity. Interestingly, in group IC1 patients (n=5), L-carnitine neither improved walking capacity nor modified the metabolic profile. Statistical analysis showed that changes in walking capacity with L-carnitine treatment were influenced exclusively by exercise-induced changes in plasma acetylcarnitine. CONCLUSIONS: In patients with intermittent claudication, assessment of plasma acetylcarnitine at rest and after exercise may be a means to select a target population for L-carnitine therapy.

Acetylcarnitine↗
PubMedDate not supplied

Carnitine balance and effects of intravenous L-carnitine in two patients receiving long-term total parenteral nutrition.

Two patients requiring total parenteral nutrition for 34 and 39 months, had plasma and urinary carnitine assays and plasma lipid assays performed before and during intravenous administration of 400 mg (2500 mumol) of L-carnitine for 7 days, followed by 40 mg (240 mumol) daily continuously. One patient had generalized lethargy and weakness which resolved within the first 5 days of carnitine administration. The plasma-free carnitine levels in this patient rose significantly. The other patient was asymptomatic and while there was no significant change in the plasma-free carnitine levels during carnitine administration, this patient remained in positive carnitine balance throughout the study. There were no significant changes in plasma lipid levels in either patient. In adult patients requiring long-term total parenteral nutrition who are otherwise normal, intravenous L-carnitine may be required to supplement the patients endogenous carnitine production.

Adult↗
PubMed2004

Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review.

Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.

Cardiotonic Agents↗
PubMed1985

Transfer and metabolism of carnitine and carnitine esters in the in vitro perfused human placenta.

The transfer and metabolism of L-carnitine, L-acetylcarnitine, and L-palmitoylcarnitine were studied in the human placenta at term by means of in vitro dual perfusion of a placental lobe. L-Carnitine transfer was 20% that of the freely diffusing antipyrine and 40% that of L-lysine. The transfer of L-acetylcarnitine was similar to that of L-carnitine, but no placental transfer of L-palmitoylcarnitine was found. In contrast to L-lysine, L-carnitine, and L-acetylcarnitine were not actively transported from the maternal to the fetal circulation. No stereospecific transfer of carnitine across the placenta was found. However, there was stereospecific uptake of carnitine by placental tissue. The placenta exhibited an active carnitine metabolism by esterifying free carnitine and hydrolyzing carnitine esters taken up from the perfusion medium and releasing the metabolites into the fetal and maternal circulations.

Acetylcarnitine↗