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Biomedical subjects

C J Rebouche

Publications and source records attributed to C J Rebouche.

At least 19 recordsLinked to original sources
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↗
PubMed1987

Measurement of epsilon-N-trimethyllysine in human blood plasma and urine.

A method for measurement of epsilon-N-trimethyllysine in human blood plasma and urine is described. An internal standard, delta-N-trimethylornithine, was added to plasma and urine specimens and the mixtures were deproteinized and/or hydrolyzed. Preliminary purification of epsilon-N-trimethyllysine and delta-N-trimethylornithine was achieved by sequential cation-exchange--anion-exchange chromatography. Amino acids in the column eluates were derivatized with o-phthalaldehyde and mercaptoethanol, and were separated by isocratic reversed-phase high-performance liquid chromatography in the presence of an ion-pairing reagent. Quantitation was achieved by post-column fluorometry. The limit of detection was 5 pmol of epsilon-N-trimethyllysine injected into the chromatograph. The procedure was suitable for determination of epsilon-N-trimethyllysine in 1 ml of plasma or 0.2-0.4 ml of urine. The method was applied to measurements of epsilon-N-trimethyllysine in plasma and urine of four systemic carnitine deficiency patients and six normal subjects. Plasma epsilon-N-trimethyllysine concentration was significantly lower in systemic carnitine deficiency patients compared to normal individuals, but no significant difference in urinary epsilon-N-trimethyllysine excretion was observed between the two groups.

Amino Acids↗
PubMed1987

Bioavailability of dietary urea nitrogen in the infant.

Because the human body has no enzymes capable of hydrolyzing urea, nitrogen from this source becomes bioavailable only by release of ammonia from urea by bacterial hydrolysis in the intestines, with subsequent absorption and utilization of ammonia. To explore extent to which urea ingested in milk becomes bioavailable, we fed di-15N-urea (both nitrogen atoms in the form of the stable isotope 15N) and determined urinary excretion of di-15N-urea (excreted without having become bioavailable) and mono-15N-urea (urea containing only one atom of 15N and therefore reflecting excretion of absorbed ammonia). The largest percentage of the ingested di-15N-urea was excreted promptly in the urine still in the form of di-15N-urea. We conclude that most of the urea ingested by a normal infant is not bioavailable.

Animals↗
PubMed1987

Evaluation of nuclear magnetic resonance spectroscopy for determination of deuterium abundance in body fluids: application to measurement of total-body water in human infants.

Nuclear magnetic resonance (NMR) spectroscopy was used to quantitate abundance of 2H in body water of human infants. This method provides precise measurement of total-body water without the extensive sample preparation requirements of previously described methods for determination of 2H content in body fluids. 2H2O (1 g/kg body weight) was administered to infants and saliva and urine were collected for up to 5 h. An internal standard was added directly to the fluid specimen and 2H enrichment in water was measured by NMR spectroscopy. Working range of deuterium abundance was 0.04-0.32 atom %. Coefficients of variation for saliva samples at 0.20 atom % 2H was 1.97%. 2H content in urine and saliva water reached a plateau by 4 h after administration, and amounts in the two fluids were virtually identical. Mean total-body water determination for six infants was 58.3 +/- 5.8% of body weight (range 53-66%).

Body Fluids↗
PubMed1987

gamma-Butyrobetaine hydroxylase activity is not rate limiting for carnitine biosynthesis in the human infant.

Carnitine biosynthesis was assessed in human infants by measuring changes in plasma carnitine concentration and rates of urinary carnitine excretion after infants were fed carnitine-free formulas with and without added epsilon-N-trimethyl-L-lysine or gamma-butyrobetaine. This study was undertaken to test the hypothesis that carnitine biosynthesis in the human infant is regulated by substrate availability rather than activity of gamma-butyrobetaine hydroxylase, the final enzyme in the carnitine biosynthetic pathway. Ten infants were fed carnitine-free formula supplemented with either 500 microM epsilon-N-trimethyl-L-lysine or 500 microM gamma-butyrobetaine for 14 d. Plasma carnitine concentration and rate of urinary carnitine excretion were measured in infants before and after this period. Plasma carnitine concentration increased twofold when infants were fed either epsilon-N-trimethyl-L-lysine and increased threefold when infants were fed gamma-butyrobetaine. The rate of carnitine excretion doubled when infants were fed epsilon-N-trimethyl-L-lysine and increased 30-fold when infants were fed gamma-butyrobetaine. Absorption of epsilon-N-trimethyl-L-lysine was verified by demonstrating increased urinary excretion of epsilon-N-trimethyl-L-lysine in infants fed this substrate. We conclude that gamma-butyrobetaine hydroxylase activity is not rate limiting for carnitine biosynthesis in the human infant. Development of renal and hepatic gamma-butyrobetaine hydroxylase activity was determined in necropsy tissue from individuals of various ages. It was verified that gamma-butyrobetaine hydroxylase activity is developmentally regulated in the liver, but not in the kidney. The clinical relevance of this observation is diminished in view of the results of the in vivo studies of carnitine biosynthesis in infants.

Adolescent↗
PubMed1986

epsilon-N-trimethyllysine availability regulates the rate of carnitine biosynthesis in the growing rat.

Rates of carnitine biosynthesis in mammals depend on the availability of substrates and the activity of enzymes subserving the pathway. This study was undertaken to test the hypothesis that the availability of epsilon-N-trimethyllysine is rate-limiting for synthesis of carnitine in the growing rat and to evaluate diet as a source of this precursor for carnitine biosynthesis. Rats apparently absorbed greater than 90% of a tracer dose of [methyl-3H]epsilon-N-trimethyllysine, and approximately 30% of that was incorporated into tissues as [3H]carnitine. Rats given oral supplements of epsilon-N-trimethyllysine (0.5-20 mg/d), but no dietary carnitine, excreted more carnitine than control animals receiving no dietary epsilon-N-trimethyllysine or carnitine. Rates of carnitine excretion increased in a dose-dependent manner. Tissue and serum levels of carnitine also increased with dietary epsilon-N-trimethyllysine supplementation. There was no evidence that the capacity for carnitine biosynthesis was saturated even at the highest level of oral epsilon-N-trimethyllysine supplementation. Common dietary proteins (casein, soy protein and wheat gluten) were found to be poor sources of epsilon-N-trimethyllysine for carnitine biosynthesis. The results of this study indicate that the availability of epsilon-N-trimethyllysine limits the rate of carnitine biosynthesis in the growing rat.

Administration, Oral↗