Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport
Journal Article
·
· J. Clin. Invest.; (United States)
The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-(methyl-3H)carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and ''other tissues'') was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-(methyl-3H)carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.
- Research Organization:
- Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota
- OSTI ID:
- 6929533
- Journal Information:
- J. Clin. Invest.; (United States), Journal Name: J. Clin. Invest.; (United States) Journal Issue: 3 Vol. 73:3; ISSN JCINA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
550501 -- Metabolism-- Tracer Techniques
550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
AMINO ACIDS
AMMONIUM COMPOUNDS
BETAINE
CARBOXYLIC ACIDS
CLEARANCE
DISEASES
DISTRIBUTION
DRUGS
ETIOLOGY
EXCRETION
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LIPOTROPIC FACTORS
MEMBRANE TRANSPORT
METABOLIC DISEASES
METABOLISM
MUSCLES
ORGANIC ACIDS
ORGANIC COMPOUNDS
QUATERNARY COMPOUNDS
TISSUE DISTRIBUTION
TRACER TECHNIQUES
TRITIUM COMPOUNDS
550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
AMINO ACIDS
AMMONIUM COMPOUNDS
BETAINE
CARBOXYLIC ACIDS
CLEARANCE
DISEASES
DISTRIBUTION
DRUGS
ETIOLOGY
EXCRETION
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LIPOTROPIC FACTORS
MEMBRANE TRANSPORT
METABOLIC DISEASES
METABOLISM
MUSCLES
ORGANIC ACIDS
ORGANIC COMPOUNDS
QUATERNARY COMPOUNDS
TISSUE DISTRIBUTION
TRACER TECHNIQUES
TRITIUM COMPOUNDS