Kegg Pathway: Alanine and aspartate metabolism

Eur J Pharmacol. 2008 Mar 18;
Chandramohan G, Ignacimuthu S, Pugalendi KV

Casearia esculenta root (Roxb.) is widely used in traditional system of medicine to treat diabetes in India. An active compound 3-hydroxymethyl xylitol (3-HMX) has been isolated and its optimum dose has been determined in a short duration study and patented. In the present study, the long-term effect of 3-HMX in type 2 diabetic rats has been investigated. An optimum dose of 3-HMX (40 mg/kg body weight) was orally administered for 45 days to streptozotocin-diabetic rats for the assessment of glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA(1c)), hepatic glycogen, and activities of carbohydrate metabolizing enzymes, such as glucokinase, glucose 6-phosphatase, fructose 1,6-bisphosphatase and glucose-6-phosphate dehydrogenase and hepatic marker enzymes, such as aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gammaglutamyl transferase (GGT) in normal and streptozotocin-diabetic rats. 3-HMX at 40 mg dose produced similar effects on all biochemical parameters studied as that of glibenclamide, a standard drug. Histological study of pancreas also confirmed the biochemical findings. These results indicate that 3-hydroxymethyl xylitol, the compound from C. esculenta, possesses antihyperglycemic effect on long-term treatment also.

J Neurochem. 2008 Jun 30;
Osborne PG, Hashimoto M

This report demonstrates that during the torpor phase of hibernation, hamsters utilize (14)C and (13)C glucose in torpor specific brain metabolic pathways. Microdialysis of (14)C glucose into the striatum rapidly induced a steady state labelling of ECF lactate and labelling of tissue GABA, glutamate (GLU), glutamine (GLN) and Alanine in ipsilateral and contralateral striata. The same tissue metabolites were labelled in cortex, hypothalamus and brainstem after microdialysis of (14)C lactate into the lateral ventricle. Serine, aspartate, glycine, taurine, tyrosine and methionine were not synthesised from glucose or lactate during torpor. ECF levels of amino and organic acids were low and unchanging during torpor and increased late during arousal to cenothermia. Labelled intracellular (14)C GABA and GLU were not communicated to the striatal ECF or ventricular space during torpor. (13)C NMR demonstrated rapid formation of lactate and functional TCA cycles in GABAergic and glutamatergic neurons, and enrichment of GLN and Alanine after IV (13)C glucose. Large changes in tissue levels of amino acids occur prior to or during entrance into torpor but not during torpor. It is proposed that cerebral intracellular dehydration, the enlargement of ECF and the biochemistries associated with brain water homeostasis may have a role in regulating hibernation.

J Gastroenterol Hepatol. 2008 Jun 25;
Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kato T, Okochi H, Ochiya T

Background and Aim: Multipotential mesenchymal stem cells (MSC), present in many organs and tissues, represent an attractive tool for the establishment of a successful stem cell-based therapy in the field of regeneration medicine. Adipose tissue mesenchymal stem cells (AT-MSC), known as adipose-derived stem cells (ASC) are especially attractive in the context of future clinical applications because of their high accessibility and minimal invasiveness during the procedure to obtain them. The goal of the present study was to induce human ASC into functional hepatocytes in vitro within a very short period of time and to check their therapeutic potential in vivo. Methods: In vitro generated ASC-derived hepatocytes were checked for hepatocyte-specific markers and functions. Afterwards, they were transplanted into nude mice with liver injury. Twenty-four hours after transplantation, biochemical parameters were evaluated in blood serum. Results: We have shown here that ASC can be differentiated into hepatocytes within 13 days and can reach the functional properties of primary human hepatocytes. After transplantation into mice with acute liver failure, ASC-derived hepatocytes can restore such liver functions as ammonia and purine metabolism. Markers of liver injury, Alanine aminotransferase, aspartate aminotransferase, as well as ammonia, were decreased after ASC-derived hepatocyte transplantation. Conclusions: Our data highlight the properties of ASC as having a special affinity for hepatocyte differentiation in vitro and liver regeneration in vivo. Thus, ASC may be a superior choice for the establishment of a therapy for injured liver.

Invest Ophthalmol Vis Sci. 2008 Jun 19;
Winkler BS, Starnes CA, Twardy BS, Brault D, Taylor RC

Purpose: To provide quantitative information on glucose utilization in cone-dominant ground squirrel retinas. Methods: Ground squirrel eyecups were incubated in media containing (14)C-glucose and the production of (14)CO2 was measured. Measurements were also made of lactic acid production (glycolysis). NMR was used to track metabolites generated from (13)C-1 glucose. Results: Ground squirrel eyecups produced lactate at a high rate and exhibited normal histology. Light-adaptation reduced glycolysis by 20%. Ouabain decreased glycolysis by 25% and decreased (14)CO2 production by 60%. Blockade of glutamate receptors had little effect on glycolysis and (14)CO2 produced. When metabolic responses were restricted to photoreceptors, light caused a 33% decrease in (14)CO2 production. The rate of (14)CO2 production was less than 10% of lactate production. Lactate was the major product formed from (13)C-glucose. Other (13)C-labeled compounds included glutamate, aspartate, glutamine, Alanine, taurine, and GABA. Lactate was the only product detected in the media bathing ground squirrel retinas. The rod-dominant rat retina exhibited a similar pattern of metabolites formed from glucose. Conclusions: Lactate, not CO2, is the major product of glucose metabolism in both ground squirrel retina and rat retina. Active Na(+) transport, however, depends more on ATP produced by mitochondria than by glycolysis. A relatively high fraction of ATP production from glycolysis and glucose oxidation continues in the absence of active Na(+) pumping and glutamatergic transmission. Major neurotransmitters are synthesized from the aerobic metabolism of glucose; anoxia-induced impairment in retinal synaptic transmission may be due to depletion of neurotransmitters.

Radiology. 2008 Jul; 248(1): 303-11
Nair RT, Silverman SG, Tuncali K, Obuchowski NA, vanSonnenberg E, Shankar S

PURPOSE: To retrospectively determine the frequency and severity of various abnormal laboratory test values following percutaneous cryoablation of liver tumors and to estimate the correlation between laboratory test values and tumor and ablation volumes. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval. Informed consent was waived. Biochemical and hematologic laboratory values from 48 procedures in 39 patients (18 men and 21 women; age range, 29-86 years) who underwent magnetic resonance (MR) imaging-guided percutaneous cryoablation of 65 liver tumors (62 metastases, three hepatocellular carcinomas) were retrospectively reviewed. Changes in laboratory values at baseline and 0-6 hours and 1-2 weeks after the procedure were analyzed with respect to tumor and ablative margin volumes by using generalized estimating equations. aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) levels were correlated with percent maximal decrease in platelet count. RESULTS: Mean ablation zone volume was 67.3 cm(3) +/- 41.2 (standard deviation) (range, 7.3-191.4 cm(3)). AST and ALT values increased after all procedures and peaked at 6 hours (median change in AST value, +835 U/L; median change in ALT value, +614.5 U/L). Platelet count decreased after 47 procedures (mean maximal decrease, 92.3 x 10(9)/L [38%]), reaching a nadir at 12-24 hours after 24 procedures (50%) and returning to normal in 31 (84%) of 37 procedures at 1-2 weeks. One procedure was complicated by disseminated intravascular coagulation that necessitated transfusion and arterial embolization. Myoglobin values increased after 21 (44%) of 48 procedures and peaked at 6 hours (trimmed-mean value, 183.4 mug/L). Ablative margin volumes were predictive of changes at 0-6 hours in AST (P = .02), ALT (P = .003), and myoglobin (P < .001) values. Percent maximal decrease in platelet count correlated with peak change in AST (r = 0.72) (P < .001). CONCLUSION: Following percutaneous cryoablation of liver tumors, alterations in liver enzymes, myoglobin, and platelet count are common, are usually self-limited, and correlate with ablative margin volume--except for changes in platelet count, which correlate with changes in AST and ALT.

Toxicol Appl Pharmacol. 2008 May 2;
Ramdhan DH, Kamijima M, Yamada N, Ito Y, Yanagiba Y, Nakamura D, Okamura A, Ichihara G, Aoyama T, Gonzalez FJ, Nakajima T

Cytochrome P450 (CYP) 2E1 was suggested to be the major enzyme involved in trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter molecular mechanism is not fully understood. The involvement of CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in cyp2e1(+/+) and cyp2e1(-/-) mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of trichloroethanol and trichloroacetic acid (TCA) were considerably greater in cyp2e1(+/+) compared to cyp2e1(-/-) mice, suggesting that CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities, cyp2e1(+/+) mice in the 2000 ppm group showed histopathological inflammation. TRI significantly upregulated PPARalpha, which might function to inhibit NFkappaB p50 and p65 signalling. In addition, TRI-induced NFkappaB p52 mRNA, and significantly positive correlation between NFkappaB p52 mRNA expression and plasma ALT activity levels were observed, suggesting the involvement of p52 in liver inflammation. Taken together, the current study directly demonstrates that CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter.

Clin Nutr. 2008 Jun 11;
Poeze M, Luiking YC, Breedveld P, Manders S, Deutz NE

BACKGROUND & AIMS: Liver organ dysfunction is an important determinant for clinical deterioration and outcome in patients with sepsis. Although glutamate plays a central role in the metabolism of the liver, liver cellular injury during sepsis is clinically determined by plasma values of the enzymes Alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The aim of this study was to determine the predictive value of measuring the amino acids glutamate and glutamine concentrations in the early phases of septic shock. METHODS: In a prospective observational study the amino acids glutamate and glutamine were compared to the standard parameters of liver dysfunction used as predictors of outcome in patients with acute liver dysfunction as part of the development of multiple organ failure. RESULTS: Glutamate concentrations were consistently and significantly lower in non-survivors (p=0.03) compared to surviving septic patients. Plasma Glu/Gln ratio was consistently lower in non-survivors compared to survivors (p=0.002). Both parameters were good predictors of outcome (area under the ROC curve) 0.75 (95% CI 0.65-0.85) and 0.82 (95% CI 0.74-0.91) respectively, p<0.0001. Glutamate concentration was an independent and better risk factor for mortality compared to the liver enzyme plasma values. CONCLUSIONS: Patients who die of septic shock with acute liver dysfunction can be predicted by significantly lowered plasma glutamate concentrations and lowered glutamate/glutamine ratios already in the first 24h of septic shock.

Biochemistry. 2008 Jul 8; 47(27): 7218-27
Bhattacharjee H, Choudhury R, Rosen BP

The ArsA ATPase is the catalytic subunit of the arsenite-translocating ArsAB pump that is responsible for resistance to arsenicals and antimonials in Escherichia coli. ATPase activity is activated by either arsenite or antimonite. ArsA is composed of two homologous halves A1 and A2, each containing a nucleotide binding domain, and a single metalloid binding or activation domain is located at the interface of the two halves of the protein. The metalloid binding domain is connected to the two nucleotide binding domains through two DTAPTGH sequences, one in A1 and the other in A2. The DTAPTGH sequences are proposed to be involved in information communication between the metal and catalytic sites. The roles of Asp142 in A1 D 142TAPTGH sequence, and Asp447 in A2 D 447TAPTGH sequence was investigated after altering the aspartates individually to Alanine, asparagine, and glutamate by site-directed mutagenesis. Asp142 mutants were sensitive to As(III) to varying degrees, whereas the Asp447 mutants showed the same resistance phenotype as the wild type. Each altered protein exhibited varying levels of both basal and metalloid-stimulated activity, indicating that neither Asp142 nor Asp447 is essential for catalysis. Biochemical characterization of the altered proteins imply that Asp142 is involved in Mg (2+) binding and also plays a role in signal transduction between the catalytic and activation domains. In contrast, Asp447 is not nearly as critical for Mg (2+) binding as Asp142 but appears to be in communication between the metal and catalytic sites. Taken together, the results indicate that Asp142 and Asp447, located on the A1 and A2 halves of the protein, have different roles in ArsA catalysis, consistent with our proposal that these two halves are functionally nonequivalent.

Neurosci Lett. 2008 Jul 18; 439(3): 245-9
Szyndler J, Maciejak P, Turzyńska D, Sobolewska A, Lehner M, Taracha E, Walkowiak J, Skórzewska A, Wisłowska-Stanek A, Hamed A, Bidziński A, Płaźnik A

It is not well recognized how disturbances in the local metabolism of some amino acids, especially glutamate and GABA, may lead to seizures. In the presented study, we have examined changes in the hippocampal steady state concentrations of amino acids involved in pentylenetetrazole-kindled and freely moving rats. It was found that in the kindled animals, the concentration of Alanine, arginine, glutamate, aspartate and taurine was increased in the interictal period of seizures compared to the control group, whereas kindling reduced the extracellular levels of GABA. No differences between kindled and not-kindled animals in the glycine, histidine and glutamine levels were present. There also appeared an over fourfold increase of the Glu/GABA ratio, a theoretical marker of the neuronal excitation level, in the kindled animals. A multivariate classification tree analysis showed that the hippocampal concentration of taurine, together with GABA and Glu, had the relatively largest prediction accuracy in discriminating between kindled and non-kindled animals, suggesting a specific role of these amino acids in the shaping of a new equilibrium between excitatory and inhibitory processes in the hippocampus of kindled animals.

Lancet. 2008 May 31; 371(9627): 1822-3
Vento S, Nobili V

Encephale. 2008 Jan; 34(1): 61-5
Arlotto E, Felicé MP, Favre C, Bun H, Cornet M

INTRODUCTION: Elevated prevalence of somatic disorders among psychiatric patients is well known and studied since latest years. According to several studies, all-cause death risk is three to fivefold to that in the general population, and a somatic comorbidity was found in 30 to 60% of patients hospitalized in a psychiatric hospital, but was unknown in 50% of cases. OBJECTIVE: Our aim was to evaluate the interest of admission blood sampling analyses for the detection of somatic comorbidity, such as impaired glucose tolerance, diabetes mellitus, lipid abnormalities or infectious diseases among hospitalized psychiatric patients. DESIGN: During three months, laboratory tests (blood cell count, glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, sodium, potassium, chlorine, urea, creatinine, Alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, and TSH) were determined in admission blood samples from 366 patients of two psychiatric hospitals. Then, according to the blood results, other biological tests (iron, ferritin, etc.) were made. RESULTS: For 194 of the 366 blood samples included (53%), at least one biological abnormality was detected. Moreover, variations in haematological variables, glucose and lipid concentrations were the most frequent. We found that 45 (10.6%) of the patients had impaired glucose tolerance (glycaemia > or =1.10 g/l), 21 (5.7%) had glycaemia > or =1.26 g/l, and 76 (23%) had dyslipidemia (HDL-cholesterol < or =0.40 g/l, LDL-cholesterol > or =1.60 g/l, or triglycerides > or =1.50 g/l). None of them had used glucose or cholesterol lowering drugs before the blood sampling. Furthermore, low haemoglobin concentrations were detected in 34 patients (9.3%) and high white cell counts (above 12 g/l) in 26 patients (7.1%). CONCLUSION: Despite methodological limits, these results showed the frequency of somatic comorbidity in patients hospitalized in psychiatric hospitals. Thus, admission blood sampling would be likely to improve the detection of somatic disorders, such as diabetes mellitus, dyslipidemia, or infectious diseases.

Biol Trace Elem Res. 2008 May 28;
Birkner E, Grucka-Mamczar E, Kasperczyk S, Kasperczyk A, Stawiarska-Pięta B, Zalejska-Fiolka J, Birkner B

Three-month studies were performed on 18 adult rabbits of New Zealand breed divided into three groups, with six animals in each: a control group on standard diet, a cholesterol group receiving 500 mg of cholesterol/100 g of feed per rabbit per 24 h (CH group), and a cholesterol + fluorine group (CH + F group) receiving 500 mg of cholesterol/100 g of feed per rabbit per 24 h and 3 mg of F(-)/kg of body weight per 24 h. The conducted studies proved that cholesterol in the applied dosage (500 mg cholesterol per rabbit per 24 h) has an atherogenic action. Fluoride ions administered together with a 500-mg cholesterol atherogenic diet inhibit the atheromatosic changes in the aorta. The concentration of plasma cholesterol was elevated in both study groups when compared to the control group but decreased in the CH + F group when compare to the CH group. The influence of fluoride ions has been examined upon the activity of Alanine aminotransferase, aspartate aminotransferase, and glutamate dehydrogenase (GLDH) in the plasma in the liver of rabbits in the course of experimental hypercholesterolemia. Increase in the activity of study enzymes has been observed in the blood plasma, which may be due to damage occurring to hepatocytes of the animals examined (a statistically significant increase in the activity of GLDH in the plasma). In the liver, the inhibition of activity for all examined enzymes has been observed in the group of rabbits with hypercholesterolemia, which testifies the disturbances in protein metabolism in examined animals. The addition of sodium fluoride to the diet rich in cholesterol results in "removing the block" on those activities, which increase. We suppose that the permeability of the hepatocyte membrane was elevated, so the activities of examined enzymes increased in the plasma ("escape" to plasma). On the one hand, fluoride ions result in probable lesion of hepatocytes membranes; on the other hand, they inhibit the atheromatosic changes in the aorta.

Toxicology. 2008 Jul 10; 249(1): 75-84
Lee MH, Hong I, Kim M, Lee BH, Kim JH, Kang KS, Kim HL, Yoon BI, Chung H, Kong G, Lee MO

Methotrexate (MTX) is used to treat a variety of chronic inflammatory and neoplastic diseases. However, it can induce hepatotoxicity such as microvesicular steatosis and necrosis. To explore the mechanisms of MTX-induced hepatic steatosis, we used microarray analysis to profile the gene expression patterns of mouse liver after MTX treatment. MTX was administered orally as a single dose of 10mg/kg (low dose) or 100mg/kg (high dose) to ICR mice, and the livers were obtained 6h, 24h, and 72h after treatment. Serum Alanine aminotransferase, aspartate aminotransferase and triacylglycerol levels were not significantly altered in the experimental animals. Signs of steatosis were observed at 24h after administration of high dose of MTX. From microarray data analysis, 908 genes were selected as MTX-responsive genes (P<0.05, two-way ANOVA; cutoff >/=1.5-fold). Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis revealed that the predominant biological processes associated with these genes are response to unfolded proteins, phosphate metabolism, and cellular lipid metabolism. Functional categorization of these genes identified 28 genes involved in lipid metabolism that was interconnected with the biological pathways of biosynthesis, catabolism, and transport of lipids and fatty acids. Taken together, these data provide a better understanding of the molecular mechanisms of MTX-induced steatogenic hepatotoxicity, and useful information for predicting hepatotoxicity through pattern recognition.

J Bacteriol. 2008 Jul; 190(14): 4859-64
Gross C, Felsheim R, Wackett LP

l-(-)-Azetidine-2-carboxylate (AC) is a toxic, natural product analog of l-proline. This study revealed the genes and biochemical strategy employed by Pseudomonas sp. strain A2C to detoxify and assimilate AC as its sole nitrogen source. The gene region from Pseudomonas sp. strain A2C required for detoxification was cloned into Escherichia coli and sequenced. The 7.0-kb region contained eight identifiable genes. Four encoded putative transporters or permeases for gamma-amino acids or drugs. Another gene encoded a homolog of 2-haloacid dehalogenase (HAD). The encoded protein, denoted l-azetidine-2-carboxylate hydrolase (AC hydrolase), was highly overexpressed by subcloning. The AC hydrolase was shown to catalyze azetidine ring opening with the production of 2-hydroxy-4-aminobutyrate. AC hydrolase was further demonstrated to be a new hydrolytic member of the HAD superfamily by showing loss of activity upon changing aspartate-12, the conserved active site nucleophile in this family, to an Alanine residue. The presence of a gene encoding a potential export chaperone protein, CsaA, adjacent to the AC hydrolase gene suggested that AC hydrolase might be found inside the periplasm in the native Pseudomonas strain. Periplasmic and cytoplasmic cell fractions from Pseudomonas sp. strain A2C were prepared. A higher specific activity for AC hydrolysis was found in the periplasmic fraction. Protein mass spectrometry further identified AC hydrolase and known periplasmic marker proteins in the periplasmic fraction. A model was proposed in which AC is hydrolyzed in the periplasm and the product of that reaction is transported into and further metabolized in the cytoplasm.

J Hazard Mater. 2008 Apr 11;
Dai R, Liu H, Qu J, Zhao X, Hou Y

A Microcystis aeruginosa which produced high content of microcystin-LR (MC-LR) but no microcystin-RR (MC-RR) was isolated from Dianchi Lake in China. In the molecular structure of MC-LR, glutamic acid, aspartic acid, leucine, Alanine and arginine are the constitutional components which are abundant in natural water. In this paper, effects of six amino acids at their natural concentrations on the growth of the M. aeruginosa and the microcystin (MC) production were studied in batch culture. M. aeruginosa could assimilate Alanine, leucine and arginine as sole nitrogen sources for growth and MC production. However, glutamic acid, aspartic acid and lysine could not be assimilated quickly, although they could pass the cell membrane and enter into the cell rapidly. Our experiment demonstrated that the possible reason of such phenomenon was that different amino acids had different effects on the process of metabolism through the free dissolved amino acids within the cells.

Ann Med. 2008; 40(5): 395-400
Takaike H, Uchigata Y, Iwamoto Y, Imagawa A, Iwahashi H, Kanatsuka A, Kawasaki E, Kobayashi T, Shimada A, Shimizu I, Maruyama T, Hanafusa T, Makino H

BACKGROUND AIMS: A mild increase in liver enzyme levels is sometimes observed in patients with diabetic ketosis or ketoacidosis. The aim of the present study was to assess the cause and prevalence of the elevation of liver transaminase levels in fulminant and acute-onset type 1 diabetic patients experiencing diabetic ketosis or ketoacidosis. METHODS: We analyzed data on the liver transaminase levels of 108 patients over 18 years of age with newly diagnosed type 1 diabetes complicated by ketosis or ketoacidosis. The data were collated from a nationwide survey on fulminant type 1 diabetes and retrospective medical records. RESULTS: Thirty-two (60.4%) out of the 53 patients suffering from fulminant type 1 diabetes were detected with transient elevation of liver transaminase (TELT) levels during the first month after initiation of insulin therapy; in the case of acute-onset type 1 diabetes, such an observation was noted in 16 (29.1%) out of 55 patients. Fatty liver was diagnosed in 20% of the patients, and 65% of these patients exhibited TELT. The dosage of insulin injected in these patients was significantly high. CONCLUSIONS: High blood glucose and fatty liver may influence the elevation of liver transaminase levels during the treatment of new-onset type 1 diabetes.

Pediatr Crit Care Med. 2008 Mar; 9(2): 209-16
Jeschke MG, Finnerty CC, Kulp GA, Przkora R, Mlcak RP, Herndon DN

OBJECTIVE: Recombinant human growth hormone (rhGH) is a salutary modulator of posttraumatic metabolic responses. However, rhGH administration is associated with deleterious side effects, such as hyperglycemia, increased free fatty acids, and triglycerides, which limit its use. Administration of beta-blocker attenuates cardiac work and resting energy expenditure after severe thermal injury and improves fat metabolism and insulin sensitivity. Therefore, the combination of rhGH plus propranolol appears ideal. The aim of the present study was to determine whether rhGH plus propranolol improves hypermetabolism and the inflammatory and acute phase response after severe burn without causing adverse side effects. DESIGN: Prospective randomized control trial. SETTING: Shriners Hospitals for Children. PATIENTS: Fifteen pediatric patients with burns > 40% total body surface area, 0.1-16 yrs of age, admitted within 7 days after burn. Fifteen children were matched for burn size, age, gender, inhalation injury, and infection and served as controls. INTERVENTIONS: Patients in the experimental group received rhGH (0.2 mg/kg/day) and propranolol (to decrease heart rate by 15%) for > or = 15 days. MEASUREMENTS AND MAIN RESULTS: Outcome measurements included resting energy expenditure, body composition, acute phase proteins, and cytokines. Both cohorts were similar in age, burn size, gender, and accompanying injuries. Percent predicted resting energy expenditure significantly decreased in patients receiving rhGH/propranolol (Delta -5% +/- 8%) compared with controls (Delta +35% +/- 20%) (p < .05). rhGH/propranolol administration significantly decreased serum C-reactive protein, cortisone, aspartate aminotransferase, Alanine aminotransferase, free fatty acids, interleukin-6, interleukin-8, and macrophage inflammatory protein-1beta when compared with controls, while growth hormone/propranolol increased serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, growth hormone, prealbumin, and interleukin-7 when compared with placebo (p < .05). CONCLUSIONS: rhGH in combination with propranolol attenuates hypermetabolism and inflammation without the adverse side effects found with rhGH therapy alone.

Physiol Chem Phys Med NMR. 2006; 38(2): 77-83
Jeong SY, Lim JS, Park HJ, Cho JW, Rana SV, Yoon S

Acetaminophen (APAP) is one of the most commonly used drugs for the safe and effective treatment of fever and pain. However, it is a well-established hepatotoxin. The objective of this study was to identify alternation in various genes in liver of mice after administration of low and high doses of APAP. Male C57BL/6J mice received APAP (30 or 300 mg/kg, i.p.). They were sacrificed after 6 hr and 24 hr for assessment of Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total RNA isolation, cDNA microarray analysis and histopathological analysis of liver injury. Low dose of APAP did not cause hepatotoxicity in mice. However, it was toxic at a high dose. Using microarray technology, we selected changed genes more than 1.5 fold. Gene expression changes were recorded even at a low dose treatment with APAP. Six (6) hr after APAP treatment at low dose, 6 genes were up-regulated and 25 genes were down-regulated. However, 24 hr after treatment at low dose 8 genes were up-regulated and 34 genes were down-regulated. 6 hr after of high dose treatment 29 genes were down-regulated and none was up-regulated. A 24 hr treatment with high dose up-regulated 6 genes and down-regulated 18 genes. These expression patterns provide information on high versus low dose mechanisms of APAP toxicity. Gene expression signatures recorded after a nontoxic dose of APAP strongly support the validity of gene expression changes as meaningful markers of hepatotoxicity.

Am J Clin Nutr. 2008 May; 87(5): 1141-7
Gasteyger C, Larsen TM, Vercruysse F, Astrup A

BACKGROUND: Weight loss was shown to be associated with improvements in liver enzymes and improvements of nonalcoholic fatty liver disease. However, some evidence also shows that liver enzymes may transiently increase immediately after a dietary-induced weight loss. OBJECTIVE: The aim was to assess the outcome of liver enzymes after a low-calorie diet (LCD) as well as during a follow-up period and to identify predictors for potential changes in these liver enzymes. DESIGN: In this post hoc analysis of an existing database, liver enzymes were assessed before and immediately after a highly standardized soy-based meal replacement LCD providing 800 kcal/d, as well as 32 and 60 wk after the end of the LCD. RESULTS: Data emanating from 147 obese subjects (104 women and 43 men) without known hepatic disease were included in this study. The LCD led to a median weight loss of 12.1 kg (range: 7.7-27.6 kg). In men, a significant decrease in Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was observed immediately after the LCD, whereas, in women, these enzymes increased significantly, although mildly; however, this increase was transient. Sex was the only identifiable predictor of these changes in liver enzymes. CONCLUSIONS: This study showed that mild, transient increases in ALT and AST values can be observed immediately after an LCD in women, but not in men. These changes are probably of multifactorial origin and may be considered as benign as long as they remain transient.

J Anim Sci. 2008 May 9;
Regmi PR, Dixon WT, Oba M

To determine the effects of ammonia load on glucose metabolism in ruminant small intestinal tissues, duodenal mucosal cells (DMC) were isolated from growing female sheep (n = 10; 46.0 +/- 0.8 kg BW) fed diets differing in CP content; high (19.4%) vs. low (13.1%). Ammonia concentration in the duodenal digesta fluid was higher for sheep fed a high CP diet compared to those fed a low CP diet (16.4 +/- 1.0 vs. 9.1 +/- 1.8 mM). The isolated primary mucosal cells were incubated for 90 min with [2-(13)C] glucose (3 mM) and ammonium chloride (0, 0.1, 1, 5, 10, 20, or 50 mM) in Krebs-Ringer HEPES buffer. It was hypothesized that DMC would increase glucose carbon utilization for the synthesis of non-essential AA when the ammonia concentration in the incubation media increased. However, utilization of glucose carbon for Alanine synthesis decreased linearly (P = 0.03) as the ammonia concentration in the incubation media increased. Furthermore, glucose disappearance and utilization of glucose carbon for aspartate synthesis were not affected (P > 0.47) by the ammonia concentration. Contrarily, in vitro glucose disappearance was greater (P = 0.03) for DMC isolated from sheep fed a low CP diet vs. a high CP diet (14.6 +/- 1.6 vs. 8.6 +/- 1.3 nmol.(10(6) cells)(-1).(90 min)(-1)), and hexokinase activity was greater (P = 0.01) in the mucosa of sheep fed a low CP diet compared to a high CP diet (1.22 +/- 0.05 vs. 1.04 +/- 0.02 mUnit/mg protein). These observations indicate that ammonia load does not affect the extent of glucose utilization by DMC, and that glucose carbon may not play a significant role for the synthesis of Alanine, aspartate, or glutamate when DMC are exposed to increased concentrations of ammonia.