Biochemical evidence of carnitine effect on propionate elimination

Sugiyama, Naruji; Morishita, Hideko; Nagaya, Sachiko; Nakajima, Takeshi; Kawase, Atsushi; Ohya, Atsushi; Sugiyama, Satoru; Kamiya, Kazuko; Watanabe, Isamu; Togari, Hajime; Kobayashi, Masanori; Ogawa, Yutaka; Wada, Yoshiro

doi:10.1007/bf01801775

Cited by 11 publications

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“…The data presented are consistent with previous studies of plasma concentrations and urinary excretion of carnitine in propionic acidemia showing a decrease in free carnitine and an increase in acylcarnitines (2)(3)(4)(5). In one patient, a skeletal muscle specimen showed a decrease in total, free, short-chain acyl-and long-chain acylcarnitines (2).…”

Section: Discussionsupporting

confidence: 91%

“…This study demonstrates that the alterations in carnitine and its derivatives observed in plasma and urine reflect the same type of altered distribution in tissue and provides further data on the effects of L-carnitine therapy. (Pediatr Res 26: 63-66, 1989) Systemic carnitine insufficiency has been implied in patients with propionic aciduria and other primary disorders of organic acid metabolism based on measurement of carnitine and its derivatives in plasma and urine (1)(2)(3)(4)(5)(6)(7)(8)(9). These studies have provided some insight into the biochemical pathophysiology of these inborn errors of metabolism as well as a rationale for their treatment with L-carnitine.…”

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confidence: 99%

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Metabolic Studies of Carnitine in a Child with Propionic Acidemia

et al. 1989

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ABSTRACT. Carnitine metabolism was studied in a 7-y- CASE HISTORY old boy with propionic acidemia due to an almost total deficiency of propionyl-CoA carboxylase. The initial diagnosis was made at 3 wk of age followed by numerous episodes of metabolic acidosis despite a low-content branch-chain amino acid diet containing supplemental biotin. Although clinically stable and in a nonacidotic state, the plasma concentration of total carnitine was normal (38.9 fiM; normal = 46 f 10, mean f SD, n = 30) whereas free carnitine was decreased (5.7 pM, normal = 37 f 8) and short-chain acylcarnitines were increased (28.6 pM; normal = 5.7 2 3.5). Skeletal muscle and liver specimens obtained at open biopsy had low total and free carnitine contents and increased ratio of short-chain acylcarnitines to free carnitine. Short-chain acylcarnitine content was low in liver but increased in skeletal muscle. The liver contained fatty vacuoles, enlarged mitochondria with paracrystalline inclusions, and numerous peroxisomes whereas the skeletal muscle also had lipid vacuoles and an increase in number and size of mitochondria. A carnitine challenge test (100 mg L-carnitinelkg body wt via a gastrostomy tube) resulted in a peak plasma carnitine concentration at 120 min. With maintenance therapy of 100 mg L-carnitine/kg/day the plasma free carnitine remained relatively low, the plasma glycine concentration decreased, and urinary acylcarnitine excretion increased. This study demonstrates that the alterations in carnitine and its derivatives observed in plasma and urine reflect the same type of altered distribution in tissue and provides further data on the effects of L-carnitine therapy. (Pediatr Res 26: 63-66, 1989) Systemic carnitine insufficiency has been implied in patients with propionic aciduria and other primary disorders of organic acid metabolism based on measurement of carnitine and its derivatives in plasma and urine (1-9). These studies have provided some insight into the biochemical pathophysiology of these inborn errors of metabolism as well as a rationale for their treatment with L-carnitine.Our report of a patient with propionic acidemia shows that plasma and urinary measurements of carnitine and acylcarnitines reflect tissue levels of carnitine compounds. It also provides additional evidence of a generalized disturbance in carnitine metabolism in organic acidurias that is amenable to carnitine therapy.The patient was a 7-y-old boy with propionic acidemia due to an almost complete absence of propionyl-CoA carboxylase activity. He presented at 10 days of age with hyperammonemia and metabolic acidosis and was treated with peritoneal dialysis. Plasma and urinary glycine were elevated, and urinary organic acid analysis demonstrated prominent excretion of propionic acid metabolites, including methylcitrate. The enzymatic diagnosis was established in cultured fibroblasts in the laboratory of Dr. L. Sweetman, University of California, San Diego, and there was no clinical response to biotin therapy.He subsequently had numerous episo...

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Metabolic Studies of Carnitine in a Child with Propionic Acidemia

et al. 1989

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“…Carnitine has been shown to be efficacious when administered to patients with a variety of disorders of organic acid metabolism (Allen et al, 1982;Seccombe et al, 1982;Chalmers et al, 1983Chalmers et al, , 1984aRoe et al, 1983Roe et al, , 1984aDiDonato et al, 1984;Sugiyama et al, 1984). The hypothesized mechanism for carnitine's action in these patients involves generation of acylcarnitines, with the resulting removal of acyl-CoAs permitting a partial normalization of hepatic function (Seccombe et al, 1982;Roe et al, 1983Roe et al, , 1984aChalmers et al, 1983Chalmers et al, , 1984aDiDonato et al, 1984;Sugiyama et al, 1984;Stumpf et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

“…In the hereditary organic acidaemias, specificenzymedeficiencies result in an accumulation of organic acids, which is associated with the clinical disease symptomatology. Several reports have demonstrated that patients with hereditary organic acidaemias can develop a secondary carnitine deficiency, and that administration of camitine to these patients results in marked clinical improvement (Allen et al, 1982;Chalmers et al, 1983Chalmers et al, , 1984aRoe et al, 1983Roe et al, , 1984aDiDonato et al, 1984;Sugiyama et al, 1984). Evidence suggests that carnitine's efficacy is a result of acylcarnitine formation from the acyl-CoAs that accumulate secondary to the metabolic defect (Seccombe et al, 1982;Roe et al, 1983Roe et al, , 1984aDiDonato et al, 1984;Sugiyama et al, 1984;Chalmers et al, 1984a,b;Stumpfet al, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…Several reports have demonstrated that patients with hereditary organic acidaemias can develop a secondary carnitine deficiency, and that administration of camitine to these patients results in marked clinical improvement (Allen et al, 1982;Chalmers et al, 1983Chalmers et al, , 1984aRoe et al, 1983Roe et al, , 1984aDiDonato et al, 1984;Sugiyama et al, 1984). Evidence suggests that carnitine's efficacy is a result of acylcarnitine formation from the acyl-CoAs that accumulate secondary to the metabolic defect (Seccombe et al, 1982;Roe et al, 1983Roe et al, , 1984aDiDonato et al, 1984;Sugiyama et al, 1984;Chalmers et al, 1984a,b;Stumpfet al, 1985). This may remove acyl-CoAs that are metabolic inhibitors, such as propionyl-CoA (Glasgow & Chase, 1976;Gregersen, 1979Gregersen, , 1981Stumpfet al, 1980), as well as liberating CoA for utilization in other biochemical pathways not affected by the primary defect.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of oxidative metabolism by propionic acid and its reversal by carnitine in isolated rat hepatocytes

Brass¹,

Fennessey²,

Miller³

1986

Biochemical Journal

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The present study was designed to study the interaction of propionic acid and carnitine on oxidative metabolism by isolated rat hepatocytes. Propionic acid (10 mM) inhibited hepatocyte oxidation of [1-14C]-pyruvate (10 mM) by 60%. This inhibition was not the result of substrate competition, as butyric acid had minimal effects on pyruvate oxidation. Carnitine had a small inhibitory effect on pyruvate oxidation in the hepatocyte system (210 + 19 and 184 + 18 nmol of pyruvate/60 min per mg of protein in the absence and presence of 10 mM-carmitine respectively; means +S.E.M., n = 10). However, in the presence of propionic acid (10 mM), carnitine (10 mM) increased the rate of pyruvate oxidation by 19%. Under conditions where carnitine partially reversed the inhibitory effect of propionic acid on pyruvate oxidation, formation of propionylcarnitine was documented by using fast-atom-bombardment mass spectroscopy. Propionic acid also inhibited oxidation of [1-14C]palmitic acid (0.8 mM) by hepatocytes isolated from fed rats. The degree of inhibition caused by propionic acid was decreased in the presence of 10 mM-carnitine (41 % inhibition in the absence of carnitine, 22% inhibition in the presence of carnitine). Propionic acid did not inhibit [1-14C]palmitic acid oxidation by hepatocytes isolated from 48 h-starved rats. These results demonstrate that propionic acid interferes with oxidative metabolism in intact hepatocytes. Carnitine partially reverses the inhibition of pyruvate and palmitic acid oxidation by propionic acid, and this reversal is associated with increased propionylcamitine formation. The present study provides a metabolic basis for the efficacy of carnitine in patients with abnormal organic acid accumulation, and the observation that such patients appear to have increased carnitine requirements ('carnitine insufficiency').

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Mouse albino‐deletions: From genetics to genes in development

1992

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Six essential genes located near the mouse albino locus have been identified as required during specific periods of development, Amongst these six, each is required either during the preimplantation stages of development, at specific times during gastrulation, within 12 hrs after birth or during juvenile development. These genes were identified as a result of extensive genetic complementation analysis using embryos homozygous for the albino deletions. Although, in principal, the associated developmental abnormalities could result from loss of multiple genes, the deletion phenotype in one case is identical to that induced by chemical mutagenesis. These results indicate that the abnormalities observed in deletion homozygotes may result from single gene loss. The deletions have proven useful not only as genetic tools to localize the position of the genes, but also as molecular entry points to the regions containing these genes. The current methodology being used to isolate candidate genes from the albino region is also reviewed here.

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Biochemical evidence of carnitine effect on propionate elimination

Cited by 11 publications

References 5 publications

Metabolic Studies of Carnitine in a Child with Propionic Acidemia

Metabolic Studies of Carnitine in a Child with Propionic Acidemia

Inhibition of oxidative metabolism by propionic acid and its reversal by carnitine in isolated rat hepatocytes

Mouse albino‐deletions: From genetics to genes in development

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