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Biomedical subjects

A L Carter

Publications and source records attributed to A L Carter.

At least 19 recordsLinked to original sources
PubMed2000

beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter.

Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na(+)-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These antibiotics possess a quaternary nitrogen as does carnitine. Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine. Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)-independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements. These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.

Acetylcarnitine↗
PubMed1999

Carnitine transport and its inhibition by sulfonylureas in human kidney proximal tubular epithelial cells.

The kidney plays an important role in the homeostasis of carnitine by its ability to reabsorb carnitine almost completely from the glomerular filtrate. The transport process responsible for this reabsorption has been investigated thus far only in laboratory animals. Here we report on the characteristics of carnitine uptake in a proximal tubular epithelial cell line derived from human kidney. The uptake process was found to be obligatorily dependent on Na+ with no involvement of anions. The process was saturable, with a Michaelis-Menten constant of 14 +/- 1 microM. The Na+:carnitine stoichiometry was 1:1. The same process also was found to be responsible for the uptake of acetylcarnitine and propionylcarnitine, two acyl esters of carnitine with potential for therapeutic use in humans. The uptake process was specific for carnitine and its acyl esters. Betaine, a structural analog of carnitine, interacted with the uptake process to a significant extent. The present studies also showed that sulfonylureas, oral hypoglycemic agents currently used in the management of type 2 diabetes, inhibited the carnitine uptake system. Among the sulfonylureas tested, glibenclamide was the most potent inhibitor. The inhibition was competitive. Glibenclamide inhibited the uptake not only of carnitine but also of acetylcarnitine and propionylcarnitine. The inhibition most likely was the result of direct interaction of the compound with the carnitine transporter because the inhibition could be demonstrated in purified rat kidney brush border membrane vesicles.

Administration, Oral↗
PubMed1999

Acetyl- L -carnitine decreases glycation of lens proteins: in vitro studies.

Although the role of carnitine system in the ocular tissues is not clearly understood, earlier studies showed that lenticular levels of L -carnitine were the highest among ocular tissues and there was a dramatic depletion of lenticular L -carnitine and acetyl- L -carnitine in streptozotocin-diabetic rats. As protein glycation has been implicated in the development of several diabetic complications including cataracts, this study was initiated to show the possible effects of L -carnitine and acetyl- L -carnitine on the glycation and advanced glycation (AGEs) of lens proteins. Calf lens soluble fraction (crystallins) was incubated with 50 m m glucose (containing14C glucose) with or without 5-50 m ml -carnitine, 5-50 m m acetyl- L -carnitine and 5-50 m m acetyl salicylic acid, for 15 days. The results show that while L -carnitine did not have any effect on in vitro glycation of lens crystallins, acetyl- L -carnitine and acetyl salicylic acid decreased crystallin glycation by 42% and 63%, respectively-this decrease was concentration dependent. Glycated crystallins were separated on HPLC which showed that the rate of glycation is in the following order: alpha>beta>gamma. Interestingly, acetyl- L -carnitine inhibited glycation of alpha crystallin more than other crystallins. In vitro incubations with [3H-acetyl] acetyl- L -carnitine showed that acetyl- L -carnitine acetylates lens crystallins (non-enzymatically) and alpha crystallin is the major acetylated protein. Furthermore, there was a 70% reduction in anti-AGE antibody reactivity when 50 m m acetyl- L -carnitine was included in the incubation of lens crystallins and 10 m m erythrose, suggesting that inhibition of glycation by acetyl- L -carnitine also affected the generation of AGEs. This in vitro study shows, for the first time, that acetyl- L -carnitine could acetylate potential glycation sites of lens crystallins, and protect them from glycation-mediated protein damage.

Acetylation↗
PubMed1996

Sodium-dependent carnitine transport in human placental choriocarcinoma cells.

The JAR human placental choriocarcinoma cells were found to transport carnitine into the intracellular space by a Na(+)-dependent process. The transport showed no requirement for anions. The Na+-dependent process was saturable and the apparent Michaelis-Menten constant for carnitine was 12.3 +/- 0.5 microM. Na+ activated the transport by increasing the affinity of the transport system for carnitine. The transport system specifically interacted with L-carnitine, D-carnitine, acetyl-DL-carnitine and betaine. 6-N-Trimethyllysine and choline had little or no effect on carnitine transport. Of the total transport measured, transport into the intracellular space represented 90%. Plasma membrane vesicles prepared from JAR cells were found to bind carnitine in a Na(+)-dependent manner. The binding was saturable with an apparent dissociation constant of 0.66 +/- 0.08 microM. The binding process was specific for L-carnitine, D-carnitine, acetyl-DL-carnitine, and betaine. 6-N-Trimethyllysine and choline showed little or no affinity. It is concluded that the JAR cells express a Na(+)-dependent high-affinity system for carnitine transport and that the Na(+)-dependent high-affinity carnitine binding detected in purified JAR cell plasma membrane vesicles is possibly related to the transmembrane transport process.

Binding Sites↗
PubMed1995

Biosynthesis and metabolism of carnitine.

This review article presents the biosynthesis, metabolism, sources, levels, and general functions of carnitine. Emphasis is placed on the expression of carnitine deficiency and insufficiency as well as the causes of these conditions. The various functions of carnitine are discussed as they may relate to disease treatment.

Animals↗
PubMed1989

Adult-onset chorea and dementia with propionic acidemia.

Propionic acidemia usually presents in the newborn period with severe metabolic acidosis and lethargy. A 31-year-old man with adult onset chorea and dementia had propionic acidemia due to propionyl CoA carboxylase deficiency. Metabolic investigations may prove useful in patients with movement disorder of unknown etiology.

Adult↗
PubMed1989

Kearns-Sayre syndrome and complex II deficiency.

A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short stature, ataxia, cardiac conduction defects, and pigmentary retinopathy. Muscle biopsy revealed ragged-red fibers. Electron microscopy showed increased numbers of mitochondria with disordered structure and paracrystalline inclusions. Enzymatic analysis revealed a deficiency of complex II of the mitochondrial respiratory chain, and, more specifically, a deficiency of succinic dehydrogenase, although both subunits of this enzyme proved to be present by immunologic analysis. Therapy with vitamin cofactors did not result in short-term improvement. This appears to be the first report of complex II deficiency in a patient with KSS.

Adult↗
PubMed1988

A factor in human seminal plasma which affects carnitine accumulation in bovine epididymal sperm.

This study was initiated to determine whether factors are present in human sperm-free seminal plasma (HSP) that regulate the uptake and release of carnitine from sperm. Bovine caput epididymal sperm cells accumulated more carnitine than caudal sperm cells. A significant reduction in carnitine uptake by caput sperm was observed in the presence of HSP from normal subjects, but not from three subjects with reduced motility. A factor has been isolated from HSP that inhibits carnitine uptake by caput sperm and has the following properties: it is nondialyzable, stable to freeze-thawing, soluble in 60% ammonium sulfate, and has an approximate molecular weight of 158 kd. These data are consistent with the existence of a relatively high molecular weight protein in HSP responsible for the preservation of carnitine concentrations in sperm.

Animals↗
PubMed1987

Localization of gamma-butyrobetaine hydroxylase in the rat testis.

The activity of gamma-butyrobetaine hydroxylase in testes is comparable on a protein basis to the amount of activity found in liver and accounts for a significant amount of the total activity found in the rat. The enzyme is localized to the seminiferous tubules of the testes. In attempting to further localize this enzyme, activity remained the same when reported on a protein basis in cryptorchid testes as compared to controls, and activity was found in bovine sperm cells obtained from the caput epididymis. These results are consistent with the localization of this enzyme in both the Sertoli cells and the germ cells.

Animals↗
PubMed1986

Anticonvulsive drugs and blood levels of lactate, pyruvate, and glucose in children with seizures.

Lactate, pyruvate, and glucose were determined in groups of 10 patients, each receiving single drug therapy for their seizure disorder with either phenytoin, valproic acid, carbamazepine, or phenobarbital, and in patients not taking medication. All drug levels were in their therapeutic ranges. The characteristics of the groups were similar, except for the phenytoin group being significantly older. No significant differences were found in glucose or pyruvate concentrations. However, patients on valproic acid had reduced lactate (p less than 0.05) and L/P ratios (p less than 0.05). The reduction in lactate in patients on valproate therapy may mask inborn errors of metabolism that normally result in an increase in blood lactate levels.

Anticonvulsants↗
PubMed1985

Serum carnosinase deficiency: a non-disabling phenotype?

Serum carnosinase deficiency (McKusick 21220) is a rare condition, described in 13 cases. Ten additional individuals with serum carnosinase deficiency have been identified. All continued to excrete increased amounts of carnosine in their urine despite a meat-free diet for 3 days. Serum carnosinase activity ranged from 0-30% of normal. In four individuals a normal Km for carnosine of 0.12 mM was observed, while in five individuals an increased Km was found. Homocarnosine levels in CSF in three individuals ranged from 3.4 to 15 mM. Clinical symptoms in these individuals were as follows: attention deficit disorder: 4; non progressive developmental delay: 1; neurofibromatosis: 1; absences seizures: 1; severe, but non-progressive mental retardation, seizures and neurosensory hearing loss: 1; progressive childhood dementia; 1; clinically normal: 1. There was no correlation between severity and type of the neurological symptoms and residual serum carnosinase activity. Although a definite conclusion can only be made after a considerably higher number of individuals has been analyzed, the suspicion that serum carnosinase deficiency is unrelated to the neurological symptoms is strengthened by these observations. There may, however, be an association with a predisposition for mental deficiency.

Carnosine↗
PubMed1984

Reconstitution of ornithine transport in liposomes with Lubrol extracts of mitochondria.

The ornithine translocase of beef liver mitochondria was extracted with Lubrol WX and reconstituted in liposomes. The uptake of ornithine by the reconstituted vesicles followed Michaelis-Menten kinetics, and was dependent on the intraliposomal pH, the time of sonication of the reconstituted liposomes and the phospholipid to detergent ratio. It is concluded that the ornithine translocator can be reconstituted, which makes the purification of this translocator feasible.

Amino Acid Transport Systems, Basic↗
PubMed1984

Further evidence for a separate enzymic entity for the synthesis of homocitrulline, distinct from the regular ornithine transcarbamylase.

Differential digitonin extraction of rat liver mitochondria and of mitochondria of livers of affected and unaffected male sparse fur mice released a lysine transcarbamylase activity from the mitochondria at a digitonin to protein ratio in between that for myokinase and glutamate dehydrogenase, but at a slightly lower ratio than the ornithine transcarbamylase activity. Homocitrulline formation by isolated rat liver mitochondria is independent of the uptake of lysine by mitochondria as evidenced by the insensitivity of homocitrulline formation to changes in the matrix pH, in contrast to citrulline formation from ornithine. High-performance liquid chromatography separates the lysine transcarbamylase activity from the ornithine transcarbamylase activity. It is concluded that the lysine transcarbamylase activity is localized outside the inner mitochondrial membrane.

Animals↗
PubMed1983

Using isokinetic dynamometry to test ambulatory patients with multiple sclerosis.

This study was designed to 1) determine whether isokinetic dynamometry is appropriate and safe for ambulatory patients with multiple sclerosis and 2) describe the idiosyncrasies the patients with multiple sclerosis exhibited during testing. Ten patients with multiple sclerosis and 20 healthy subjects were matched for age, sex, and weight. The isokinetic peak torque and endurance measurements of knee extensor and knee flexor muscles were recorded at selected angular velocities ranging from 0 to 275 degrees/sec and extensor:flexor muscle strength ratios were calculated. Statistical analysis (t tests) revealed that both the extensor and flexor muscle peak torque values for patients with multiple sclerosis were significantly lower than those for healthy subjects at all angular velocities (p less than .005 to p less than .001), and yet were similar in shape and slope. Mean extensor:flexor ratios for healthy subjects and for patients with multiple sclerosis were not significantly different at 70, 190, and 230 degrees/sec. Individual chart recordings identified any contractile difficulties or increased contraction time. Isokinetic testing is judged to be a safe and reliable form of objective neuromuscular testing for ambulatory patients with multiple sclerosis.

Adult↗
PubMed1983

Effects of acute moderate-intensity exercise on carnitine metabolism in men and women.

The purpose of this investigation was to describe the dynamics of carnitine metabolism during an acute episode of exercise. Twenty-eight subjects (14 male; 14 female) exercised for 40 min on a bicycle ergometer at 55% of their maximal aerobic capacities. Blood samples were obtained at rest, 10, 20, 30, and 40 min of exercise, and 15-min postexercise. Muscle biopsies of the vastus lateralis were performed before and after exercise. Results demonstrated that the percent of acylated plasma carnitine increased significantly (P less than 0.05) across all subjects from 17.3% at rest to 22.3% by 40 min of exercise and continued to increase to 22.8% 15-min postexercise. Total muscle carnitine levels fell significantly (P less than 0.001) across all subjects from 4.21 (1.27) (means +/- SD) mumol/g wet weight at rest to 3.29 (1.27) mumol/g wet weight after exercise. Well-trained males and females had almost identical levels of muscle carnitine [4.35(1.86) and 4.34 (0.64) mumol/g wet weight, respectively]. These levels were somewhat higher but not significantly higher than their moderately trained counterparts [3.86(1.34) and 4.28(1.18) males and females, respectively]. Carnitine palmitoyl transferase (E.C. 2.3.1.21) activity also declined significantly (P less than 0.05) across all subjects after exercise. This study is the first to demonstrate a potential loss of acylated carnitine forms from muscle to plasma during acute exercise, possibly reflecting an increase in carnitine turnover. Alterations in carnitine status may represent another metabolic adaptation to chronic exercise training.

Adult↗