Increased urinary excretion of dicarboxylic acids and 4-hydroxyphenyllactic acid in patients with Zellweger syndrome.
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Biomarkers↗
Biomedical subjects
E Mayatepek
Publications and source records attributed to E Mayatepek.
Increased generation of cysteinyl leukotrienes in Kawasaki disease.
Endogenous cysteinyl leukotriene synthesis was assessed in 10 patients with Kawasaki disease and 10 healthy controls by measuring excretion of leukotriene E4 (LTE4) in urine. LTE4 was increased more than fivefold in patients with Kawasaki disease compared with controls (median (range) 55.3 (31.8-120.6) v 10.2 (7.1-14.9) nmol/mol creatinine); this suggests that cysteinyl leukotrienes are involved in the pathophysiology of Kawasaki disease. Leukotriene synthetase inhibition or receptor antagonism may therefore offer a new potential therapeutic approach in children with this disease.
Child, Preschool↗
Leukotrienes: biosynthesis, metabolism, and pathophysiologic significance.
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Animals↗
No evidence for inhibition of human glutathione reductase by valproic acid.
The human red blood cell enzyme glutathione reductase (GR) was reported to be inhibited by the anticonvulsant drug valproic acid (VPA) [Cotariu et al., Biochem Pharmacol 43: 425-429, 1992]. When attempting to reproduce and extend these experiments, we could not detect any significant effect of VPA on glutathione reductase in haemolysates from 20 healthy children and 10 children under VPA therapy, no matter which concentration of the drug (0.9 or 1.8 mM in a haemolysate diluted by a factor of 50 or 1.8 mM directly in the assay), which incubation time (0-60 min) and which assay system were chosen. An influence of VPA on FAD-free apoglutathione reductase was also excluded. GR-activities of 10 children under VPA therapy (1.08 +/- 0.14 U/mL blood or 7.57 +/- 0.94 U/g Hb) were almost identical with the activities of age- and sex-matched controls (1.04 +/- 0.17 U/mL or 7.79 +/- 1.32 U/g Hb). No correlation between erythrocyte GR activity and serum levels of VPA was observed. Finally, incubation of crystalline human GR with VPA did not lead to enzyme inhibition; rather, in most experiments the enzyme was stabilized by incubation with VPA. Possible explanations for the discrepancies between the results of Cotariu et al. and our data are discussed.
Adolescent↗
SSIEM Award. Impaired metabolism of leukotrienes in inherited metabolic disorders.
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Glutathione Synthase↗
The diagnosis of pulmonary tuberculosis by gaschromatographic detection of tuberculostearic acid using flame ionisation detectors.
It has been shown that the detection of tuberculostearic acid (TBSA) with gas chromatography-mass-spectrometry provides a highly specific, sensitive and rapid method for the diagnosis of various forms of tuberculosis. However, the need for complex and expensive equipment prevented the more widespread use of this method. We report on the application of conventional gas chromatography with flame ionization detectors in the detection of TBSA in sputum samples. TBSA was detected in all patients with proven pulmonary tuberculosis before treatment or under treatment for less than 4 weeks (n = 18). Six of these patients (33%) had a negative microscopy result at the time of the study. Sputum samples from patients under therapy for longer than 4 weeks (n = 20) were TBSA-positive in 15 cases (75%). Only in two cases was the diagnosis by microscopy and/or culture not met by TBSA-detection. All sputa of 20 control patients with lung diseases other than tuberculosis were TBSA negative. Additional analysis of patients' data showed a significant relationship (P < 0.005) between the relative amounts of TBSA detectable in the sputum samples and the duration of therapy. It is concluded that conventional capillary gaschromatography may be sensitive and specific enough to be used for the detection of TBSA in sputum of patients with pulmonary tuberculosis.
Chromatography, Gas↗
Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency.
Glutathione synthetase deficiency (GSD) is an inborn error of glutathione (GSH) metabolism leading to a generalized intracellular GSH deficiency. Because GSH is required for leukotriene C4 (LTC4) synthesis, we studied synthesis and metabolism of several lipoxygenase products in two patients with GSD by radio-HPLC, UV spectrophotometry, and enzyme immunoassays. In both patients, LTC4 synthesis was significantly decreased in calcium ionophore-stimulated neutrophils (up to 0.4 ng/10(6) cells; controls, 5.0 +/- 0.9) and monocytes (up to 3.6 ng/10(6) cells; controls, 30.2 +/- 3.3). LTB4 synthesis was about seven times higher in GSD cells compared with controls, whereas synthesis of other 5-, 12-, and 15-lipoxygenase products and prostaglandin E2 was not affected. Neutrophils and monocytes from both patients showed a marked reduction in capacity to form [3H]LTC4 from [3H]LTA4 (9-14% of control values). Urinary LTE4 was finally found to be 50-fold lower in GSD, reflecting a decreased synthesis of cysteinyl LT in vivo. GSD may serve as a unique model for the linkage between LT synthesis and GSH metabolism in vivo.
Calcimycin↗
Impaired degradation of prostaglandins and thromboxane in Zellweger syndrome.
Cyclooxygenase products are metabolized by omega-oxidation as well as beta-oxidation. Children with Zellweger syndrome (ZS) are characterized by peroxisome deficiency. To evaluate the role of peroxisomal beta-oxidation on cyclooxygenase metabolites, the degradation of endogenous prostaglandin (PG) E2, prostacyclin, and thromboxane (Tx) A2 was assessed in children with ZS (n = 7) and in healthy children (n = 7). PGE2, prostacyclin, TxB2, and their major urinary metabolites 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid, 2,3-dinor-6-oxo-PGF1 alpha, and 2,3-dinor-TxB2, respectively, were measured in urine by gas chromatography-mass spectrometry/mass spectrometry. The median excretion of healthy children was 17.9 ng of 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid/mg creatinine (interquartile range, 6.3 to 19.4 ng/mg), 0.38 ng of 2,3-dinor-6-oxo-PGF1 alpha/mg creatinine (interquartile range, 0.34 to 0.70 ng/mg), and 0.36 ng of 2,3-dinor-TxB2/mg creatinine (interquartile range, 0.14 to 0.54 ng/mg). In contrast, none of these metabolites could be detected in urine of children with ZS (p < 0.002). However, we identified in the urine of these children a new metabolite of PGE2 as 11-hydroxy-9,15-dioxo-prost-5-en-1,20-dioic acid by gas chromatography-mass spectrometry, and we confirmed the presence of 9,11-dihydroxy-15-oxo-prost-5-en-1,20-dioic acid the main urinary metabolite of PGF2 alpha in ZS. Importantly, these two metabolites were only detectable in urine of children with ZS.(ABSTRACT TRUNCATED AT 250 WORDS)
Biotransformation↗
Leukotrienes in the pathophysiology of kwashiorkor.
The actions of cysteinyl leukotrienes include production of oedema. We investigated whether these mediators might be involved in the oedematous malnutrition syndrome kwashiorkor. The capacity of leukotriene (LT) synthesis by stimulated whole blood and urinary LTE4 excretion was measured in 12 children with kwashiorkor, and compared with that in 24 marasmic and 12 control children. Urinary LTE4 excretion was significantly higher in patients with kwashiorkor than in controls (118.8 [SD 28.5] vs 31.1 [19.3] nmol/mol creatinine; p < 0.01). Whole blood LTE4 synthesis was increased in kwashiorkor patients by a factor of 3.5 (p < 0.01). In marasmic children, LTE4 excretion and synthesis did not differ from those in controls. Although glutathione, known to participate in LTC4 synthesis, was subnormal in erythrocytes of all malnourished patients, whole-blood LTC4 synthesis was higher in kwashiorkor patients than in controls (28.1 [5.0] ng/mL; p < 0.05), and close to control values (9.8 [1.5] ng/mL) in marasmic children. LTB4 synthesis, however, was greatly reduced in kwashiorkor patients (11.5 [2.4] vs 46.5 [6.4] ng/mL; p < 0.01). Inability to synthesise the immunoregulator LTB4 may lead to inefficient chemoattraction of phagocytes and an inadequate inflammatory response in kwashiorkor. The increased endogenous cysteinyl LT generation in kwashiorkor suggests that these lipid mediators are involved in the pathophysiology of the syndrome, particularly in oedema formation.
Child, Preschool↗
Increased excretion of endogenous urinary leukotriene E4 in extrahepatic cholestasis.
The cysteinyl leukotrienes LTC4, LTD4 and LTE4 are potent lipid mediators eliminated from the blood circulation mainly due to uptake by the liver and the kidneys. In man hepatobiliary elimination of cysteinyl leukotrienes predominates over renal excretion. In the present study, the urine from patients with extrahepatic cholestasis (n = 25) and age- and sex-matched healthy control subjects (n = 25) was analyzed for endogenous LTE4, the predominant metabolite of LTC4 excreted into urine. LTE4 was separated by reversed-phase high-performance liquid chromatography and subsequently quantified by enzyme immunoassay. Healthy subjects excreted a median concentration of 14 nmol LTE4/mol creatinine (range 5-24 nmol/mol creatinine). Its median concentration increased significantly to more than 5-fold higher levels to 74 nmol LTE4/mol creatinine (range 52-93 nmol/mol creatinine) in patients with extrahepatic cholestasis (P < 0.01). These results indicate that extrahepatic cholestasis leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney with subsequent increased excretion of LTE4 into urine.
Adolescent↗
Peroxisomal leukotriene degradation: biochemical and clinical implications.
Degradation of the cysteinyl leukotrienes LTE4 and N-acetyl-LTE4, and of LTB4 by beta-oxidation from the omega-end has been recognized as an important pathway in the inactivation of these mediators. The contribution of peroxisomes to leukotriene degradation and inactivation was studied in isolated hepatocytes, in isolated liver peroxisomes, and in patients with inherited peroxisome deficiency. (1) Isolated hepatocytes from rats pretreated with the peroxisome proliferator clofibrate produced highly increased amounts of beta-oxidation products derived from omega-carboxy-LTB4 and omega-carboxy-N-acetyl-LTE4 as compared to normal hepatocytes. (2) Isolated peroxisomes purified from normal and clofibrate-treated liver produced omega-carboxy-dinor-LTB4 and omega-carboxy-tetranor-LTB3 when nucleotide cofactors, including CoA, ATP, NAD+, FAD, and NADPH, were added. beta-Oxidation of the cysteinyl leukotriene omega-carboxy-N-acetyl-LTE4 was observed only with isolated peroxisomes together with a microsome fraction providing an acyl-CoA synthetase activity. (3) Peroxisomal leukotriene-binding proteins were identified by photo-affinity labeling with omega-carboxy-[3H]leukotrienes and precipitation of labeled polypeptides with antibodies against enzymes of the peroxisomal beta-oxidation system. (4) Peroxisomal degradation of leukotrienes in humans was studied by analyses of endogenous leukotrienes and their catabolites in urine from patients with an inherited peroxisomal deficiency disorder (Zellweger syndrome) and healthy infant controls. Urinary LTE4, relative to creatinine, was increased 10-fold in the patients, whereas the beta-oxidation product omega-carboxy-tetranor-LTE3 was only detectable in healthy infants. In addition, LTB4 was exclusively detected in the urine of patients with peroxisome deficiency. The increased levels of biologically active, proinflammatory mediators might be of pathophysiological significance. In addition, the altered pattern of leukotriene metabolites in urine may be of diagnostic value. The measurements in these patients underline the essential role of peroxisomes in the catabolism and inactivation of leukotrienes in humans.
Animals↗
Enhanced urinary excretion of leukotriene E4 in patients with mevalonate kinase deficiency.
In patients with mevalonate kinase deficiency, urinary excretion of the leukotriene LTE4 was found to be elevated. A positive linear relationship between increased urinary excretion of mevalonate and LTE4 (n = 5) suggests that increased cysteinyl leukotriene synthesis is involved in the pathomechanisms of this disease.
Child↗
Deafness, complement deficiencies and immunoglobulin status in patients with meningococcal diseases due to uncommon serogroups.
The prevalence of deafness and complement deficiencies in association with meningococcal disease caused by uncommon serogroups of meningococci was studied in 30 patients (Group A) and 30 controls with Serogroup B disease (Group B). In Group A 8 patients (26.6%) had hearing impairment in contrast to only 1 patient (3.3%) in Group B (P < 0.01). Complement deficiency was detected in 8 patients (26.6%) of Group A whereas none of the Group B patients showed a defect in the complement system (P < 0.01). Association between complement deficiencies and meningococcal disease was detected for Serogroups Y (n = 5; 16.6%) and W135 (n = 3; 10.0%). Localization of the defects revealed only complement deficiencies of the classical pathway (C8-beta or C7 defects). The levels of Ig and IgG subclasses were found to be within the normal range for all patients. Our results suggest that meningococcal diseases caused by uncommon serogroups are more often associated with deafness and late complement component defects.
Blotting, Western↗
Impaired degradation of leukotrienes in patients with peroxisome deficiency disorders.
The degradation of leukotrienes by beta-oxidation from the omega-end proceeds in peroxisomes (Jedlitschky et al. J. Biol. Chem. 1991. 266:24763-24772). Peroxisomal degradation of leukotrienes was studied in humans by analyses of endogenous leukotrienes in urines from eight patients with biochemically established peroxisome deficiency disorder and eight age- and sex-matched healthy infant controls. Leukotriene metabolites were separated by high-performance liquid chromatography, quantified by radioimmunoassays, and identified as well as quantified by gas chromatography-mass spectrometry. Urinary leukotriene E4 (LTE4) and N-acetyl-LTE4 excretions, relative to creatinine, were increased > 10-fold in the patients in comparison to healthy infants. The beta-oxidation product omega-carboxy-tetranor-LTE3 averaged 0.05 mumol/mol creatinine in the controls but was not detectable in the patients. However, omega-carboxy-LTE4 (median 13.6 mumol/mol creatinine) was significantly increased in the patients' urine, whereas LTB4 (median 0.07 mumol/mol creatinine) and omega-carboxy-LTB4 were detected exclusively in the urines of the patients. These data indicate an impairment of the inactivation and degradation of both LTE4 and LTB4 in patients with peroxisomal deficiency. The increased levels of the biologically active, proinflammatory mediators LTE4 and LTB4 might be of pathophysiological significance in peroxisome deficiency disorders. This is the first and so far only condition with a pronounced urinary excretion of omega-carboxy-LTE4, omega-carboxy-LTB4, and LTB4. This impaired catabolism of leukotrienes and the altered pattern of metabolites may be of diagnostic value. These findings underline the essential role of peroxisomes in the catabolism of leukotrienes in humans.
Chromatography, High Pressure Liquid↗
Deficient synthesis of cysteinyl leukotrienes in glutathione synthetase deficiency.
Glutathione synthetase deficiency (GSD) is an inborn error of glutathione (GSH) metabolism. As a consequence of the block in the gamma-glutamyl cycle, the enzyme defect leads to a generalized intracellular GSH deficiency. The cysteinyl leukotrienes (LTs), LTC4, LTD4 and LTE4, are potent lipid mediators generated in the 5-lipoxygenase pathway. LTC4 is derived from the unstable epoxide LTA4 by conjugation with GSH, and therefore GSH is required for LTC4 synthesis. In the circulation LTC4 is rapidly metabolized to LTE4 which is excreted in the urine. In the present study, LT metabolites were separated in a patient with biochemically established GSD and intracellular GSH deficiency (0.5 mM in erythrocytes, normal range 2.0-2.5 mM) by reversed-phase high-performance liquid chromatography, and quantified by enzyme immunoassays. Our results revealed that in GSD LTC4 synthesis is significantly decreased in calcium ionophore A23187-activated monocytes as well as in neutrophils (11-14% and 7-10%, respectively, of the levels detected in the parents or healthy controls). Additionally, urinary LTE4 was also found to be abnormally decreased in GSD (0.4 nmol/mol creatinine as compared to 15-46 nmol/mol creatinine in parents and controls). GSD represents the first described disorder with decreased synthesis of cysteinyl LTs and may serve as a unique model for the linkage between LT synthesis and GSH metabolism in vivo. Moreover the impaired synthesis of cysteinyl LTs might be involved in the pathophysiology of GSD.
Cysteine↗
Prevalence of enteropathogenic and enterotoxigenic Escherichia coli in children with and without diarrhoea in Esteli, Nicaragua.
In Esteli, Las Segovias, Nicaragua, the frequency of isolations of enteropathogenic (EPEC), and enterotoxigenic E. coli (ETEC) was investigated in 100 children with (n = 50) and without diarrhoea (n = 50). EPEC was found to be significantly (p < 0.05) more frequent in diarrhoeal (16%) than in healthy children (4%). Detailed analyses revealed that 6 serotypes of E. coli were involved. Isolation of ETEC was not statistically significantly different (p > 0.05) in diarrhoeal (28%) and healthy children (16%). Determination of the susceptibility of isolated E. coli indicated a high level of resistance to common antimicrobial drugs. These resistant strains of E. coli might become a health problem in this part of Nicaragua.
Child, Preschool↗
Clinical and biochemical phenotype in 11 patients with mevalonic aciduria.
OBJECTIVE: Mevalonic aciduria is a consequence of the deficiency of mevalonate kinase, the first enzyme after 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the biosynthesis of cholesterol and nonsterol isoprenes. To establish the clinical and biochemical phenotype of mevalonic aciduria, the authors assembled their experience with 11 patients including attempts at therapeutic interventions. METHODS: Mevalonic acid in body fluids was determined by stable isotope dilution gas chromatography/mass spectroscopy with selected ion monitoring, ubiquinone-10 concentrations by reversed-phase high-pressure liquid chromatography. RESULTS: Varying degrees of severity of clinical illness were observed despite uniform, virtual absence of residual activity of the enzyme. The most severely affected patients have had profound developmental delay, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, and anemia, as well as diarrhea and malabsorption, and have died in infancy. Less severely affected patients have had psychomotor retardation, hypotonia, myopathy, and ataxia. All patients have had recurrent crises in which there was fever, lymphadenopathy, increase in size of liver and spleen, arthralgia, edema, and a morbilliform rash. Neuroimaging studies revealed selective and progressive atrophy of the cerebellum. Mevalonic acid concentrations were found to be grossly elevated in body fluids of all patients. Concentrations of plasma cholesterol were normal or only slightly reduced. Concentrations of ubiquinone-10 in plasma were found to be decreased in most patients. Abnormalities such as hypoglycemia, metabolic acidosis, or lactic acidemia, the usual concomitants of disorders of organic acid metabolism, were conspicuously absent. CONCLUSIONS: These observations establish the broad range of clinical symptoms and biochemical findings in mevalonic aciduria. It is concluded that although patients with mevalonic aciduria have a recognizable phenotype of serious clinical manifestations, some patients are likely to remain undiagnosed and may be found in a variety of subspecialty clinics, including neurology, gastroenterology, cardiology, and genetics.
Abnormalities, Multiple↗
Transport and in vivo elimination of cysteinyl leukotrienes.
Transport processes control not only synthesis and release of LTC4 but also the elimination and excretion of LTC4 and its metabolites. (i) A primary-active ATP-dependent export carrier mediates the release of LTC4 from a leukotriene-generating cell, as exemplified by mastocytoma cells, and as measured in mastocytoma plasma membrane vesicles (2). (ii) Release of cysteinyl leukotrienes into the blood circulation is followed by a rapid elimination with an initial half-life of 38 sec in rats and 4.0 min in man, as measured with the labeled, representative LTC4 catabolite, N-acetyl-LTE4. (iii) 11C-labeled N-acetyl-LTE4 can serve for non-invasive studies on cysteinyl leukotriene elimination and excretion by the liver and kidney in the intact organism using positron emission tomography. An impairment of leukotriene transport from the liver across the canalicular membrane into bile, studied in mutant rats and in extrahepatic cholestasis, leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney. N-Acetyl-LTE4 labeled with a short-lived positron-emitting isotope provides quantitative insight into the pathways of cysteinyl leukotriene elimination in vivo. (iv) Cysteinyl leukotriene export from the liver into bile is mediated by an ATP-dependent primary-active export carrier. This decisive step in cysteinyl leukotriene elimination has been characterized in hepatocyte canalicular membrane vesicles (3). The leukotriene exporter is deficient in transport mutant rats. The leukotriene carrier is distinct from other ATP-dependent export carriers identified in this membrane domain, such as the ATP-dependent bile salt export carrier (25) and the multidrug export carrier (27).
Adenosine Triphosphate↗