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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. Am J Clin Nutr 1993;58:868-72.

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.

An infant diet of cow's milk causes blood loss through the gastrointestinal tract. In a study to determine the nature and extent of this problem, 52 infants at 168 days of age were placed on a diet of either cow's milk or milk-based formula. The trial was conducted until they reached 252 days of age. Of these infants, 31 had been breast fed and 21 had been fed formula. Periodically, fecal and blood samples were obtained from the infants. The introduction of cow's milk led to a marked increase in guaiac-positive stools. (Guaiac is a substance used to test for the presence of occult blood, or blood not visible to the naked eye. A guaiac-positive result indicates the presence of blood.) The proportion of guaiac-positive stools in the cow's milk fed babies increased to 30.3 percent during the first 28 days of the study, compared with 3 percent in the same infants prior to the trial of cow's milk. Only 5 percent of the formula-fed infants had guaiac-positive stools during the trial. Those infants who were fed soy-protein formulas prior to the trial were more prone to have guaiac-positive stools when fed cow's milk than those who had been fed milk based formulas. The stools of infants fed cow's milk showed a significantly higher hemoglobin, or red blood cell concentration, than before the trial; among these infants the stool hemoglobin concentration was higher in those who had previously been breast fed. The study did not show a deterioration in the iron status of the babies, except in one infant who became markedly iron deficient and two others who developed minor iron deficiencies. The serious iron deficiency was attributed to gastrointestinal blood loss. The adverse effects of cow's milk continue during infancy and early childhood, but even particularly sensitive children can tolerate cow's milk later in life. It has also been demonstrated that heating cow's milk inactivates the substance that causes blood loss. (Consumer Summary produced by Reliance Medical Information, Inc.)

L-Carnitine is a normally occurring compound associated with essential metabolic steps involving aerobic breakdown of fatty acids. The compound is vital in the moving of fatty acids into a particular subcellular organelle (discrete microscopic structure), the mitochondrion. Most individuals in the course of their normal diet take in carnitine in excess of their requirements, and the kidneys also work to conserve carnitine in the body. As a result, deficiencies of carnitine are exceedingly uncommon; however, there are reports of low blood concentrations of carnitine in studies conducted in both India and Thailand. There is also concern that individuals who place themselves on self-selected low-carnitine diets may develop deficient states. Because dietary carnitine is primarily obtained from meats and dairy products the levels of carnitine in persons eating a strict vegetarian, lactoovovegetarian (those who also eat dairy products and eggs), and a standard North American mixed diet were compared. Data derived from children were considered separately from adults. The data show that adults who followed both strict vegetarian and lactoovovegetarian diets had lower levels of blood carnitine than persons who ate the standard mixed diet. There were no statistical differences between the two vegetarian regimens. In children, however, there were clear statistical differences in the blood and urine carnitine level of all three groups. There is no indication that the small differences seen in adults indicates a dietary deficiency in carnitine. Whether the larger differences in carnitine levels of children relates to a dietary deficiency for carnitine is currently unknown.

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 γ-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 γ-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 γ-butyrobetaine remained unchanged. The plasma concentrations and urinary output of L-lysine and -N-trimethyllysine remained unchanged within each group before and after treatment. A positive linear correlation was found between urinary -N-trimethyllysine and 3-methylhistidine output, indicating that the rate of -N-trimethyllysine excretion correlates with the amount of 3-methylhistidine liberated by protein turnover. The data indicate that generation of -N-trimethyIlysine probably depends on protein breakdown but its use for carnitine synthesis is not necessarily regulated by carnitine status.

ABSTRACT: 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 ?-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 ?-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 ?-butyrobetaine remained unchanged. The plasma concentrations and urinary output of L-lysine and ?-N-trimethyllysine remained unchanged within each group before and after treatment. A positive linear correlation was found between urinary ?-N-trimethyllysine and 3-methylhistidine output, indicating that the rate of ?-N-trimethyllysine excretion correlates with the amount of 3-methylhistidine liberated by protein turnover. The data indicate that generation of ?-N-trimethyIlysine probably depends on protein breakdown but its use for carnitine synthesis is not necessarily regulated by carnitine status.

Depletion of intramembranous particles has been reported in the muscle fiber plasma membrane in Duchenne dystrophy. We searched for a similar abnormality in plasma membranes of cultured muscle cells obtained from six patients with Duchenne dystrophy and six controls. A precise method for phase microscopic to freeze-fracture electronmicroscopic correlation was devised to identify the cell of origin of each replicated membrane face. For both control and patient cells, P-face particle density was higher in myotubes than in mononuclear cells. However, there were no significant differences between control and dystrophic cells when comparing pfaces of myotubes, E faces of myotubes, pfaces of single cells, or E faces of single cells. The frequency distribution of particle diameters was similar in pfaces of control and Duchenne myotubes. Other structural features of the freeze-fractured plasma membrane also were similar.

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 ε-N-trimethyl-L-lysine or γ-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 γ-butyrobetaine hydroxylase, the final enzyme in the carnitine biosynthetic pathway. Ten infants were fed carnitine-free formula supplemented with either 500 µMε-N-trimethyl-L-lysine or 500 µMγ-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 γ-N-trimethyl-L-lysine and increased threefold when infants were fed γ-butyrobetaine. The rate of carnitine excretion doubled when infants were fed ε-N-trimethyl-L-lysine and increased 30-fold when infants were fed γ-butyrobetaine. Absorption of ε-N-trimethyl-L-lysine was verified by demonstrating increased urinary excretion of ε-N-trimethyl-L-lysine in infants fed this substrate. We conclude that γ-butyrobetaine hydroxylase activity is not rate limiting for carnitine biosynthesis in the human infant. Development of renal and hepatic γ-butyrobetaine hydroxylase activity was determined in necropsy tissue from individuals of various ages. It was verified that γ-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.

Oral supplementation with L-carnitine or DL-carnitine for treatment of primary and secondary carnitine deficiency syndromes is becoming increasingly popular, yet little is known about the systemic manifestations of oral intake of large doses of those compounds, particularly the D-isomer of carnitine. To determine the possible beneficial and/or toxic effects or oral carnitine isomers and the carnitine precursor, γ-butyrobetaine, in the rat, groups of male, weanling rats were fed a carnitine-free diet (control) supplemented with various amounts of L-carnitine, D-carnitine, DL-carnitine or γ-butyrobetaine for 32 days. Rats fed diets supplemented with L-carnitine (0.1–1.0%) had increased L-carnitine concentrations in serum and all tissues studied. Mean L-carnitine concentrations in serum and tissues (except liver) from rats fed equivalent amounts of L-carnitine, as the racemic mixture DL-carnitine, were greater than controls but were consistently lower than in rats fed L-carnitine alone. D-Carnitine (1% of diet) significantly reduced serum and heart L-carnitine concentrations from control levels, and the effects of γ-butyrobetaine depended on the level of dietary supplementation. Dietary L-carnitine, D-carnitine and γ-butyrobetaine (1%) reduced carnitine biosynthesis from ε-N-trimethyl-L-lysine in vivo. However, this decrease probably resulted from effects on transport of γ-butyrobetaine into tissues, rather than on the biosynthetic pathway per se. Other than mild diarrhea with high levels of some supplements, no toxic effects of these compounds were observed under the conditions employed and within the time frame of the study. However, the negative effects of high levels of dietary γ-butyrobetaine and D-carnitine on tissue L-carnitine concentrations observed in this study may presage more severe systemic alterations over a longer period of time.

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 є-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]є-N-trimethyllysine, and approximately 30% of that was incorporated into tissues as [3H]carnitine. Rats given oral supplements of є-N-trimethyllysine (0.5–20 mg/d), but no dietary carnitine, excreted more carnitine than control animals receiving no dietary є-N-trimethyllysine or carnitine. Rates of carnitine excretion increased in a dose-dependent manner. Tissue and serum levels of carnitine also increased with dietary є-N-trimethyllysine supplementation. There was no evidence that the capacity for carnitine biosynthesis was saturated even at the highest level of oral є-N-trimethyllysine supplementation. Common dietary proteins (casein, soy protein and wheat gluten) were found to be poor sources of є-N-trimethyllysine for carnitine biosynthesis. The results of this study indicate that the availability of є-N-trimethyllysine limits the rate of carnitine biosynthesis in the growing rat.

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, ɛ-N-trimethyllysine or γ-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 γ-butyrobetaine dramatically increased camitine production, ɛ-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 γ-butyrobetaine hydroxylase. Carnitine synthesis from exogenous ɛ-N-trimethyllysine is limited either by enzymatic processes that lead to the final intermediate, γ-butyrobetaine, or by the ability of this substrate to enter tissues capable of carrying out these transformations.