Biomedical subjects

C J Rebouche

Publications and source records attributed to C J Rebouche.

At least 19 recordsLinked to original sources

PubMed1999

Effect of long-term valproic acid administration on the efficiency of carnitine reabsorption in humans.

To elucidate the etiology of valproic acid-induced carnitine deficiency, we tested the hypothesis that long-term valproic acid administration decreases the rate of carnitine reabsorption. Thirteen healthy men participated in a 34-day protocol in which carnitine clearance was measured before and after 28 days of valproic acid administration. During valproic acid administration (days 6 to 33), plasma free and total carnitine concentrations decreased (18% and 12%, respectively, P<.05) by 16 days, but returned to pretreatment concentrations by 28 days. From day 14 to day 30, the rate of free carnitine excretion was 50% lower than at baseline (day 4, P<.05). Free and total carnitine clearance, indexed to the glomerular filtration rate, was lower after valproic acid administration (P<.01). Contrary to our hypothesis, after 28 days of valproic acid administration, the rate of carnitine reabsorption was enhanced independent of the glomerular filtration rate and filtered load. Changes in the plasma concentration, rate of excretion, and clearance were specific for carnitine and were not generalized in magnitude or direction to the other amino acids. We conclude that the kidney adapts to conserve carnitine during valproic acid administration and therefore does not cause valproic acid-induced carnitine depletion in adults.

Absorption↗

PubMed1998

Carnitine metabolism and its regulation in microorganisms and mammals.

In procaryotes, L-carnitine may be used as both a carbon and nitrogen source for aerobic growth, or the carbon chain may be used selectively following cleavage trimethylamine. Under anaerobic conditions and in the absence of preferred substrates, some bacteria use carnitine, via crotonobetaine, as an electron acceptor. Formation of trimethylamine and lambda-butyrobetaine (from reduction of crotonobetaine) from L-carnitine by enteric bacteria has been demonstrated in rats and humans. Carnitine is not degraded by enzymes of eukaryotic origin. In higher organisms, carnitine has specific functions in intermediary metabolism. Concentrations of carnitine and its esters in cells of eukaryotes are rigorously maintained to provide optimal function. Carnitine homeostasis in mammals is preserved by a modest rate of endogenous synthesis, absorption from dietary sources, efficient reabsorption, and mechanisms present in most tissues that establish and maintain substantial concentration gradients between intracellular and extracellular carnitine pools.

Animals↗

PubMed1995

Renal handling of carnitine in experimental vitamin C deficiency.

Experimental vitamin C deficiency is associated with carnitine concentrations in blood and some tissues, but is not due to a decreased ability of scorbutic animals to synthesize carnitine. The effect of experimental vitamin C deficiency on urinary carnitine excretion in vivo and carnitine transport into renal cortical brush-border membrane vesicles in vitro was investigated in guinea pigs fed normal and vitamin C-deficient diets for 24 days. Excretion of free and total carnitine was approximately fourfold greater in scorbutic animals as compared with normal guinea pigs during the last 6 days of the experimental regimen. The rate of carnitine transport into renal cortical brush-border membrane vesicles prepared from scorbutic animals was approximately 36% lower than the corresponding rate for vesicles prepared from normal animals. However, this effect was not specific, since rates of sodium gradient-dependent transport of glucose, lysine, and taurine (but not alanine) were also lower in vesicles prepared from scorbutic animals, although the magnitude of the decrease was less than for carnitine. The results are consistent with the hypothesis that carnitine depletion in vitamin C deficiency is due to decreased efficiency of carnitine reabsorption.

Amino Acids↗

PubMed1995

The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency.

Experimental vitamin C deficiency in guinea pigs is associated with low carnitine concentrations in blood and some tissues. Ascorbic acid is a cofactor for two enzymes in the pathway of carnitine biosynthesis. The effect of experimental vitamin C deficiency on the ability of guinea pigs to synthesize carnitine was in animals fed a vitamin C-deficient diet for 28 days. On days 19 to 28, supplements (0.5 mmol.kg body weight-1.d-1) of the carnitine precursors epsilon-N-trimethyllysine or gamma-butyrobetaine were administered orally. Ascorbate-supplemented, ascorbate-deficient, and pair-fed (to ascorbate-deficient) animals showed an increase in the rate of carnitine biosynthesis (as estimated from measured rates of carnitine excretion) of 32 to 40 mumol.kg body weight-1.d-1 following supplementation with epsilon-N-trimethyllysine. Likewise, animals in each experimental group showed an increase in the rate of carnitine biosynthesis of 41 to 50 mumol.kg body weight-1.d-1 after supplementation with gamma-butyrobetaine. These results indicate that scorbutic guinea pigs are able to synthesize carnitine at a normal or above-normal rate. For guinea pigs not given a carnitine precursor supplement, rates of free and total carnitine excretion for ascorbate-deficient (but not pair-fed) animals were threefold higher than for ascorbate-supplemented animals during days 19 to 28 of the feeding regimen. Thus, carnitine depletion in vitamin C deficiency likely is due to excessive urinary excretion of carnitine and not to a decreased rate of carnitine biosynthesis.

Analysis of Variance↗

PubMed1993

Renal adaptation to dietary carnitine in humans.

Carnitine homeostasis in humans is maintained by dietary carnitine intake, a modest rate of endogenous carnitine synthesis, and efficient conservation of carnitine by the kidney. To assess the effect of dietary carnitine on the efficiency of carnitine reabsorption in humans, rates of carnitine excretion and reabsorption, indexed to the glomerular filtration rate, were determined over a range of plasma free and total carnitine concentrations in 12 strict vegetarians before and after dietary carnitine supplementation (0.248 mmol/d). This amount of dietary carnitine supplementation did not significantly increase plasma carnitine concentration and did not alter the glomerular filtration rate. At normal physiological plasma carnitine concentrations, the rate of carnitine excretion was increased and the rate of carnitine reabsorption was decreased by carnitine supplementation. We conclude that the kidney adapts to carnitine intake by reducing the efficiency of carnitine reabsorption.

Adult↗

PubMed1993

Effect of dietary macronutrient content on carnitine excretion and efficiency of carnitine reabsorption.

We examined the effect of macronutrient content on glomerular filtration rate (GFR), and excretion, reabsorption, and filtered load of carnitine. Ten subjects consumed five diets [high protein (HP), low protein (LP), control, high fat (HF), and high carbohydrate (HC)] of equal energy and carnitine content for 6 d each, in a randomized crossover manner. The rate of carnitine excretion was lower after the LP diet than after the HP diet because of lower GFR after the LP diet. The rate of carnitine reabsorption was lower after the LP diet than after the HP diet, also because of the lower GFR after the LP diet. The rate of carnitine reabsorption was not different after the HF and HC diets, nor was GFR. The filtered load of carnitine, however, was greater after the HF diet, resulting in a higher rate of carnitine excretion.

Adult↗

PubMed1993

Relationship of carnitine and carnitine precursors lysine, epsilon-N-trimethyllysine, and gamma-butyrobetaine in drug-induced carnitine depletion.

Plasma concentrations and rates of urinary excretion of carnitine and some of its precursors were studied in three groups of children receiving drugs known to cause carnitine depletion. Patients in group A received pivampicillin and a molar equivalent of carnitine for 7 d. Patients in group B received pivampicillin with a 5.8-fold molar excess of carnitine for 1 wk. Patients in group C were treated chronically with valproic acid and received a molar equivalent (to valproic acid) of carnitine for 14 d. Patients in group A had markedly increased (16-fold) urinary carnitine ester excretion concomitant with diminished urinary free carnitine and gamma-butyrobetaine output and lower plasma free carnitine concentration. Supplementation with one molar equivalent of carnitine (to pivampicillin) was ineffective in preventing the reduction of plasma carnitine concentration observed with pivampicillin treatment alone. For group B patients, administration of excess carnitine resulted in a further increase (35-fold) of urinary carnitine ester output with no decrease of plasma carnitine concentration, urinary gamma-butyrobetaine, or free carnitine excretion. For patients in group C, the initially low plasma free and total carnitine concentrations and urinary output of carnitine and carnitine esters markedly increased with carnitine supplementation, but urinary excretion of gamma-butyrobetaine remained unchanged. The plasma concentrations and urinary output of L-lysine and epsilon-N-trimethyllysine remained unchanged within each group before and after treatment. A positive linear correlation was found between urinary epsilon-N-trimethyllysine and 3-methylhistidine output, indicating that the rate of epsilon-N-trimethyllysine excretion correlates with the amount of 3-methylhistidine liberated by protein turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1992

Carnitine function and requirements during the life cycle.

L-Carnitine has been described as a "conditionally essential" nutrient for humans. Segments of the human population suggested as having a requirement for carnitine include infants (premature and full-term), patients on long-term parenteral nutrition, and perhaps children. The evidence to support these claims includes 1) low circulating carnitine concentrations; 2) abnormal (or at least different) circulating metabolite concentrations (free fatty acids, triglycerides, ketone bodies), and 3) very limited and inconsistent growth data. A number of subjective observations and anecdotal case reports have been offered in support of a requirement for carnitine. Exogenous carnitine is required to maintain "normal" (in the epidemiologic sense) plasma or serum carnitine concentrations in humans of all ages. But "functional carnitine deficiency," defined by abnormal clinical presentation correctable by carnitine administration, has not been demonstrated in an otherwise normal (nonpathologic) population. On the other hand, nutritional or pharmacological intervention with carnitine or its esters may be beneficial for very premature infants, infants and children with various clinical conditions associated with low circulating carnitine concentrations, and in some chronic diseases associated with the aging process.

Adolescent↗

PubMed1991

Quantitative estimation of absorption and degradation of a carnitine supplement by human adults.

Results of kinetic and pharmacokinetic studies have suggested that dietary carnitine supplements are not totally absorbed, and are in part degraded in the gastrointestinal tract of humans. To determine the metabolic fate of dietary carnitine supplements in humans, we administered orally a tracer dose of [methyl-3H]L-carnitine with a meal to five normal adult males, who had been adapted to a high-carnitine diet plus carnitine supplement (2 g/d) for 14 days. Appearance of [methyl-3H]L-carnitine and metabolites in serum, and urinary and fecal excretion of radiolabeled carnitine and metabolites was monitored for 5 to 11 days following administration of the test dose. Maximum concentration of [methyl-3H]L-carnitine in serum occurred at 2.0 to 4.5 hours after administration of the tracer, indicating relatively slow absorption from the intestinal lumen. Total radioactive metabolites excreted in urine and feces ranged from 47% to 55% of the ingested tracer. Major metabolites found were [3H]trimethylamine N-oxide (8% to 49% of the administered dose; excreted primarily in urine) and [3H]gamma-butyrobetaine (0.44% to 45% of the administered dose; excreted primarily in feces). Urinary excretion of total carnitine was 16% to 23% of intake. Fecal excretion of total carnitine was negligible (less than 2% of total carnitine excretion).

Absorption↗

PubMed1991

Ascorbic acid and carnitine biosynthesis.

It has been suggested that early features of scurvy (fatigue and weakness) may be attributed to carnitine deficiency. Ascorbate is a cofactor for two alpha-ketoglutarate-requiring dioxygenase reactions (epsilon-N-trimethyllysine hydroxylase and gamma-butyrobetaine hydroxylase) in the pathway of carnitine biosynthesis. Carnitine concentrations are variably low in some tissues of scorbutic guinea pigs. Ascorbic acid deficiency in guinea pigs resulted in decreased activity of hepatic gamma-butyrobetaine hydroxylase and renal but not hepatic epsilon-N-trimethyllsine hydroxylase when exogenous substrates were provided. It remains unclear whether vitamin C deficiency has a significant impact on the overall rate of carnitine synthesis from endogenous substrates. Nevertheless, results of studies of enzyme preparations and perfused liver in vitro and of scorbutic guinea pigs in vivo provide compelling evidence for participation of ascorbic acid in carnitine biosynthesis.

Animals↗

PubMed1991

Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites.

Results of kinetic and pharmacokinetic studies have suggested that dietary carnitine is not totally absorbed and is in part degraded in the gastrointestinal tract of humans. To determine the metabolic fate of dietary carnitine in humans, we administered orally a tracer dose of [methyl-3H]L-carnitine with a meal to subjects who had been adapted to a low-carnitine diet or a high-carnitine diet. Urinary and fecal excretion of radiolabeled carnitine and metabolites was monitored for 5 to 11 d following administration of the test dose. Total radioactive metabolites excreted ranged from 13 to 34% (low carnitine diet) and 27 to 46% (high carnitine diet) of the ingested tracer. Major metabolites found were [3H]trimethylamine N-oxide (8 to 39% of the administered dose; excreted primarily in urine) and [3H]gamma-butyrobetaine (0.09 to 8% of the administered dose; excreted primarily in feces). Urinary excretion of total carnitine was 42 to 95% (high carnitine diet) and 190 to 364% (low carnitine diet) of intake. These results indicate that oral carnitine is 54 to 87% bioavailable from normal Western diets; the percentage of intake absorbed is related to the quantity ingested.

Adult↗

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↗

PubMed1990

Cow milk feeding in infancy: further observations on blood loss from the gastrointestinal tract.

Because feeding of cow milk causes normal infants to lose increased amounts of occult blood from the gastrointestinal tract, we conducted a prospective trial to measure intestinal blood loss quantitatively and to monitor iron nutritional status. Fifty-two infants entered the trial at 168 days of age and were assigned at random to receive either cow milk or a milk-based formula. Initially, 31 infants had been breast-fed and 21 had been fed formulas. With the feeding of cow milk, the proportion of guaiac-positive stools increased from 3.0% at baseline to 30.3% during the first 28 days of the trial (p less than 0.01), whereas the proportion of positive stools remained low (5.0%) with the feeding of formula. The proportion of guaiac-positive stools among cow milk-fed infants declined later, but for the entire trial it remained significantly (p less than 0.01) elevated. Stool hemoglobin concentration increased markedly with the introduction of cow milk, rising from a mean (+/- SD) of 622 +/- 527 micrograms/gm dry stool at baseline to 3598 +/- 10,479 micrograms/gm dry stool during the first 28 days of ingestion of cow milk. Among infants fed formula, stool hemoglobin did not increase and was significantly (p less than 0.01) less than in the cow milk group. Among infants fed cow milk, the increase in hemoglobin concentration tended to be greater for those who had initially been fed human milk than for those who had initially been fed formulas. Iron nutritional status was not significantly different between the two feeding groups. However, one infant became iron deficient after 4 weeks of ingesting cow milk. We conclude that cow milk feeding leads to increased intestinal tract blood loss in a large proportion of normal infants and that the amount of iron lost is nutritionally important.

Animals↗

PubMed1990

Role of carnitine in utilization of dietary medium-chain triglycerides by term infants.

The role of carnitine in oxidation of dietary medium-chain fatty acids (as medium-chain triglycerides) was studied in term human infants. Infants were fed, alternately, formulas with fat content that was predominantly long-chain triglycerides, or 40% medium-chain triglycerides. Urinary acylcarnitine excretion was significantly higher and the ratio of free to total carnitine was significantly lower when infants were fed the formula with medium-chain triglycerides. Two groups of 10 infants were fed a commercial soy-protein-based formula modified to contain 40% of fat calories as medium-chain triglycerides and with or without added L-carnitine. By 56 d, infants fed the formula without added L-carnitine excreted significantly more medium-chain dicarboxylic acids than did the same infants at 28 d and significantly more than infants consuming the carnitine-supplemented formula at either 28 or 56 d. Results are consistent with a role for carnitine in metabolism of dietary medium-chain triglycerides in infants.

Animals↗

PubMed1989

Renal conservation of carnitine by infants and adults: no evidence of developmental regulation.

To determine the efficiency of renal conservation of carnitine in infants, urinary carnitine excretion was measured at intervals in 10 infants while plasma carnitine concentration was manipulated by supplementing carnitine-free formula with 0 microM, 140 microM and 280 microM L-carnitine. As carnitine supplementation increased from 0 microM to 280 microM, fractional excretion of free carnitine increased tenfold from 0.6% to 6.0%; fractional excretion of acylcarnitine esters increased to a lesser degree (10.5-15.6%). At all supplementation levels fractional excretion of acylcarnitine esters was significantly greater than fractional excretion of free carnitine. We conclude that free and esterified carnitine are handled differently in the infant kidney. Results in infants were compared to previously reported data for adults. Mean fractional excretions of total, free and esterified carnitine by infants (7.2%, 5.4% and 12.7%, respectively) were similar to those by adults (6.5%, 5.0% and 15.0%). Thus, renal losses of carnitine apparently do not account for the low plasma carnitine concentrations observed in infants fed carnitine-free formulas.

Adult↗

PubMed1989

Low carnitine intake and altered lipid metabolism in infants.

We examined the effect of dietary carnitine on variables of lipid metabolism in human infants. Normal male full-term infants were fed an isolated soy-protein-based formula with or without added carnitine from age 6-9 d to age 112 d. Growth and food intake were measured throughout the study. At ages 56 and 112 d serum concentrations of carnitine, free fatty acids, and triglycerides and urinary excretion of carnitine and medium-chain dicarboxylic acids were measured. Serum carnitine concentrations were lower in all infants fed unsupplemented formula. There was no difference in growth or food intake between the two groups of infants. Serum free fatty acid concentrations were significantly higher in the infants not receiving dietary carnitine. Moreover, excretion of all three medium-chain dicarboxylic acids was significantly higher in infants not receiving dietary carnitine. We conclude that lack of dietary carnitine affects lipid metabolism of infants during the first 4 mo of life.

Carnitine↗

PubMed1989

Carnitine status of lactoovovegetarians and strict vegetarian adults and children.

Because carnitine is contained primarily in meats and dairy products, vegetarian diets provide a model for assessing the impact of prolonged low carnitine intake on carnitine status. Plasma carnitine concentrations and urinary carnitine excretion were measured in adults and children consuming a strict vegetarian, lactoovovegetarian, or mixed diet. In adults plasma carnitine concentration and urinary carnitine excretion of strict vegetarians and lactoovovegetarians were significantly lower than those in the mixed-diet group but were not different from each other. In children significant differences were found between all three diet groups for both plasma carnitine concentration and urinary carnitine excretion. The differences in plasma carnitine concentrations were greater in children than in adults, possibly reflecting the effects of growth and tissue deposition. Small differences between diet groups in adults do not suggest a nutritionally significant difference in carnitine status. Whether vegetarian children are at greater risk for overt deficiency is not answered.

Adolescent↗

PubMed1989

Utilization of dietary precursors for carnitine synthesis in human adults.

Endogenous synthetic pathways are presumed to be sufficient to provide adequate amounts of carnitine to meet the needs of the body. However, circulating carnitine levels of strict vegetarian adults and children, and particularly of infants fed carnitine-free formulas, are significantly lower than normal. Therefore, we investigated loci at which rates of carnitine synthesis may be restricted in human adults. Excess amounts of the carnitine precursors lysine plus methionine, epsilon-N-trimethyllysine or gamma-butyrobetaine were fed as supplements to a low carnitine diet for 10 d. Rate of carnitine synthesis was estimated by changes in carnitine excretion and changes in serum and muscle carnitine levels. Dietary gamma-butyrobetaine dramatically increased carnitine production, epsilon-N-trimethyllysine had a somewhat smaller effect, and lysine plus methionine had even less effect on carnitine synthesis. We conclude that carnitine synthesis is not limited by the activity of gamma-butyrobetaine hydroxylase. Carnitine synthesis from exogenous epsilon-N-trimethyllysine is limited either by enzymatic processes that lead to the final intermediate, gamma-butyrobetaine, or by the ability of this substrate to enter tissues capable of carrying out these transformations.

Adult↗