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Title: Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport

Abstract

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 carnitinemore » 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.« less

Authors:
;
Publication Date:
Research Org.:
Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota
OSTI Identifier:
6929533
Resource Type:
Journal Article
Journal Name:
J. Clin. Invest.; (United States)
Additional Journal Information:
Journal Volume: 73:3; Journal Issue: 3
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; BETAINE; METABOLISM; ETIOLOGY; EXCRETION; MEMBRANE TRANSPORT; METABOLIC DISEASES; MUSCLES; TISSUE DISTRIBUTION; TRACER TECHNIQUES; TRITIUM COMPOUNDS; AMINES; AMINO ACIDS; AMMONIUM COMPOUNDS; CARBOXYLIC ACIDS; CLEARANCE; DISEASES; DISTRIBUTION; DRUGS; ISOTOPE APPLICATIONS; LABELLED COMPOUNDS; LIPOTROPIC FACTORS; ORGANIC ACIDS; ORGANIC COMPOUNDS; QUATERNARY COMPOUNDS; 550901* - Pathology- Tracer Techniques; 550501 - Metabolism- Tracer Techniques

Citation Formats

Rebouche, C J, and Engel, A G. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport. United States: N. p., 1984. Web. doi:10.1172/JCI111281.
Rebouche, C J, & Engel, A G. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport. United States. https://doi.org/10.1172/JCI111281
Rebouche, C J, and Engel, A G. Thu . "Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport". United States. https://doi.org/10.1172/JCI111281.
@article{osti_6929533,
title = {Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport},
author = {Rebouche, C J and Engel, A G},
abstractNote = {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.},
doi = {10.1172/JCI111281},
url = {https://www.osti.gov/biblio/6929533}, journal = {J. Clin. Invest.; (United States)},
number = 3,
volume = 73:3,
place = {United States},
year = {1984},
month = {3}
}