Plasma and urinary levels of carnitine in different experimental models of hyperammonemia and the effect of sodium benzoate treatment

The effect of hyperammonemia on plasma and urinary levels of carnitine was studied in different groups of +/Y (normal) and spf/Y (chronically hyperammonemic) mice. Experimental models of acute and subacute hyperammonemia were prepared in +/Y and spf/Y mice by the use of ammonium acetate ip injections and arginine-free diets, respectively. In acute hyperammonemia, the plasma levels of both free and acylcarnitines increased significantly whereas acyl/free carnitine ratio was decreased, indicating a mobilization of carnitine from the storage sites. The subacute hyperammonemia model showed the same tendency in respect of plasma and urinary carnitines; however, the values in plasma were more significantly different. The effect of sodium benzoate on plasma carnitine levels, during both an acute and a prolonged treatment, consisted in a significant lowering of free carnitine and a significant increase in the acyl/free carnitine ratio, in both +/Y normal and spf/Y mouse models. The changes in the urinary profile, on benzoate treatments, were not significant. These results demonstrate the individual effects of hyperammonemia and benzoate therapy on carnitine metabolism, which may be helpful in understanding and ameliorating the therapeutic approach to hereditary hyperammonemias.     

Cell-free synthesis and transport of precursors of mutant ornithine carbamoyltransferases into mitochondria

Synthesis, mitochondrial transport and processing of ornithine carbamoyltrasferase (EC 2.1.3.3) were studied in mutant mice strains (sparse-fur, spf, and sparse-fur with abnormal skin and hair, spf-ash) which exhibit a deficiency in this enzyme. Spf mice have an increased amount (about 150% of control) of the enzyme with abnormal kinetic properties, whereas spf-ash mice have a decreased amount (about 10% of control) of the enzyme with apparently normal kinetic properties. Precursors of the mutant enzymes were synthesized in a reticulocyte lysate cell-free system. The hepatic level of translatable mRNA coding for the enzyme and the rate of the enzyme synthesis in liver slices of spf mice were 58 and 60% of the controls, respectively. In the case of spf-ash mice the activity of translatable mRNA for the enzyme was 10% of the controls. These results indicate that the decreased amount of ornithine carbamoyltransferase protein in spf-ash mice is due mainly to a decreased level of translatable mRNA for the enzyme, whereas the increase in the enzyme amount in spf mice is presumably the result of a decreased rate of enzyme degradation. The subunit molecular weight of the spf enzyme precursor was practically the same as that of the normal enzyme precursor (M_r 40 000). Both precursors synthetized in vitro could be taken up and processed similary to an apparently mature form (M_r 37 000). In the case of spf-ash enzyme, two discrete in vitro products were observed on sodium dodecyl sulfate polyacrylamide gel; one comigrated with the normal enzyme precursor and the other moved slightly slower. Both products appeared to be taken up and processed to the mature form of the enzyme.     

Significance of transported glycine in the conjugation of sodium benzoate in spf mutant mice with ornithine transcarbamylase deficiency

3H-glycine and 14C-serine were injected intraperitoneally, during treatment of spf mutant mice with 2% sodium benzoate in drinking water. Urinary hippurate was separated by thin layer chromatography and counted for 3H and 14C labels representing transported and newly synthesized glycine, respectively. The specific activity of 3H-hippurate increased significantly in mutant and normal groups, while the increase of 14C was seen only in mutants. The ratio of specific activity 3H:14C showed significant increases in normal (0.99 to 1.93; p less than 0.01) and mutant (1.53 to 3.05; p less than 0.05) groups, which shows that glycine transported from body pools played a significantly greater role in the conjugation of benzoate, compared to glycine synthesized de novo from serine. In spf mice, benzoate treatment also resulted in a decrease in orotate excretion, indicating amelioration of the hyperammonemic state. It is postulated that the elimination of glycine transported from body pools may be the primary mechanism for the reduction of ammoniagenicity in benzoate therapy, and that the de novo synthesis of glycine may have a secondary effect.     

The importance of glyoxylate and other glycine precursors in the hepatic and renal conjugation of benzoate in normal and hyperammonemic mice

Benzoate conjugation, represented by hippurate synthesis, was measured in hepatocytes isolated from normal and sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase deficiency, to compare the effects of glyoxylate and piridoxylate (a hemiacetal of glyoxylate and pyridoxine), substituted for glycine. Various amino acid precursors of glycine described in the literature, including serine, threonine, glutamine, and glutamate, were studied in a similar manner. The role of glyoxylate and piridoxylate was also assessed in the renal cortex, in comparison with liver homogenates from normal and hyperammonemic mice. The results indicate the importance of glyoxylate and piridoxylate to completely substitute for glycine (96-115%) in isolated hepatocytes of spf/Y mice, as compared with 53-69% (p less than 0.05) in normal +/Y controls. The mean value of amino acid precursors to substitute for glycine in spf mice was serine 51%, threonine 29% (p less than 0.05), and glutamine 9%. In normal mice, only serine (21%) (p less than 0.01) partly substituted for glycine, whereas threonine, glutamine and glutamate gave negative values of net hippurate synthesis. The specific activity of renal cortex for hippurate synthesis from glycine, glyoxylate and piridoxylate was 3-4 times that of liver homogenates (p less than 0.01 - less than 0.001). A scheme for the transamination of glyoxylate by alanine is presented. Besides alanine, the excess of glycine, serine, and threonine is readily deaminated in the body to take part in gluconeogenic reactions, thus contributing to hyperammonemia. The cumulative effect of benzoate conjugation to drain these ammoniagenic precursors through glycine may be the basis of its therapeutic effect in hyperammonemia.     

Hepatic mitochondrial proteins in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine

The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC), and develops hyperammonemia immediately after weaning and maintains it throughout its life span. We have studied the effects of acetyl-L-carnitine (ALCAR) on the hepatic mitochondrial proteins of the chronically hyperammonemic spf mice. Two different age groups of mice were studied, the weanlings (3 weeks) and the adult mice (8 weeks). Our results indicate that in the mitochondrial matrix, the untreated chronic hyperammonemia induced a significant increase in the quantity of 54.4-kDa protein in spf adult mice. After ALCAR treatment, in spf adult mice, the quantities of the 54.4-kDa, 63.8-kDa, and 129-kDa matrix proteins were significantly increased. In the mitochondrial inner membrane fraction of the spf weanling mice, a 53.5-kDa protein was significantly increased by ALCAR treatment. Our results show that: (a) chronic hyperammonemia has altered the mitochondrial matrix protein profile in spf mice, that (b) ALCAR has a modulating effect on various matrix and inner membrane proteins, and that (c) there was no effect of hyperammonemia or ALCAR treatment on the outer membrane proteins.     

Transient hyperammonemia during aging in ornithine transcarbamylase-deficient, sparse-fur mice

Ornithine transcarbamylase [EC 2.1.3.3] (OTC) deficient, sparse-fur (spf) mice are considered to be a good model of human OTC deficiencies. We measured the blood ammonia concentration in spf mice. It was not always at a high level. It was high only during weaning, then gradually decreased and finally fell to a normal level. A similar phenomenon was observed in the change of hepatic ammonia concentration. Excretion of urinary orotate in spf mice was 15-20 times higher than in control mice just after weaning. It also gradually decreased during aging, but remained at a high level compared with adult control mice. OTC activity at pH 7.7 in the liver of spf mice increased significantly between the weaning period and 30-40 days old, when blood ammonia was falling to a normal level.     

Efficient mitochondrial import of newly synthesized ornithine transcarbamylase (OTC) and correction of secondary metabolic alterations in spf(ash) mice following gene therapy of OTC deficiency.

BACKGROUND: The mouse strain sparse fur with abnormal skin and hair (spf(ash)) is a model for the human ornithine transcarbamylase (OTC) deficiency, an X-linked inherited urea cycle disorder. The spf(ash) mouse carries a single base-pair mutation in the OTC gene that leads to the production of OTC enzyme at 10% of the normal level. MATERIALS AND METHODS: Recombinant adenoviruses carrying either mouse (Ad.mOTC) or human (Ad.hOTC) OTC cDNA were injected intravenously into the spf(ash) mice. Expression of OTC enzyme precursor and its translocation to mitochondria in the vector-transduced hepatocytes were analyzed on an ultrastructural level. Liver OTC activity and mitochondrial OTC concentration were significantly increased (300% of normal) in mice treated with Ad.mOTC and were moderately increased in mice receiving Ad.hOTC (34% of normal). The concentration and subcellular location of OTC and associated enzymes were studied by electron microscope immunolocalization and quantitative morphometry. RESULTS: Cytosolic OTC concentration remained unchanged in Ad.mOTC-injected mice but was significantly increased in mice receiving Ad.hOTC, suggesting a block of mitochondria translocation for the human OTC precursor. Mitochondrial ATPase subunit c [ATPase(c)] was significantly reduced and mitochondrial carbamy delta phosphate synthetase I (CPSI) was significantly elevated in spf(ash) mice relative to C3H. In Ad.mOTC-treated mice, the hepatic mitochondrial concentration of ATPase(c) was completely normalized and the CPSI concentration was partially corrected. CONCLUSIONS: Taken together, we conclude that newly synthesized mouse OTC enzyme was efficiently imported into mitochondria following vector-mediated gene delivery in spf(ash) mice, correcting secondary metabolic alterations.     

The effect of phenobarbitone on cytoplasmic NADP-linked dehydrogenase activities in rat liver

Phenobarbitone administered in drinking water (0.5 g/l) or by daily intraperitoneal injection (100 mg/kg body weight) consistently caused an elevation of hepatic NADP-linked malic enzyme in rats maintained on a pellet diet. Three to four days appeared to be required for maximum response. The effect was also observed in animals maintained on a protein rich diet, in which the basic hepatic malic enzyme activity was low, but not in animals maintained on a sucrose rich diet, in which the basic enzyme activity was almost twice normal. Methyl cholanthrene, administered by daily intraperitoneal injection (40 mg/kg body weight), resulted in elevated hepatic levels not only of malic enzyme but also of the pentose phosphate pathway dehydrogenases. The timing of the "starve-refeed" response of the hepatic NADP-linked dehydrogenases in phenobarbitone-treated rats was similar to that in controls, and similar maximum enzyme activities were reached. The role of cytoplasmic NADP-linked dehydrogenases in the provision of reducing equivalent is discussed, particularly in relation to hepatic microsomal drug metabolism.     

Inhibition of <Emphasis Type="SmallCaps">d</Emphasis>-Amino-Acid Oxidase Activity Induces Pain Relief in Mice

(1). We investigated the effects of inhibiting d-amino-acid oxidase (DAO) activity on nociceptive responses through the use of mutant ddY/DAO⁻ mice, which lack DAO activity, and through the application of a selective inhibitor of DAO, sodium benzoate, in the tail flick test, hot-plate test, formalin test, and acetic acid-induced writhing test. (2). Compared with normal ddY/DAO⁺ mice, ddY/DAO⁻ mice showed significantly prolonged tail withdrawal latency in the tail flick test and licking/jumping latency in the hot-plate test, as well as significantly reduced duration of licking/biting in the late phase of the formalin test and the number of abdominal writhing in the acetic acid-induced writhing test. (3). In addition, we investigated the effects of sodium benzoate in Kunming mice having normal DAO activity. (4). Intravenous administration of sodium benzoate (400 mg/kg) significantly inhibited pain responses of the late phase of the formalin test and abdominal writhing responses in the acetic acid-induced writhing test, with no effects on the early phase flinch responses in the formalin test, nociceptive responses in the tail flick test, or hot-plate test. (5). These results suggest that DAO acts as a pro-nociceptive factor in pain, particularly chronic pain, transmission and modulation, and may be a target for pain treatment.     

Insulin receptor tyrosine kinase activity is unaltered in ob/ob and db/db mouse skeletal muscle membranes

Insulin binding and insulin receptor tyrosine kinase activity were examined in two rodent models with genetic insulin resistance using partially-purified skeletal muscle membrane preparations. Insulin binding activity was decreased about 50% in both 12-week (219 +/- 184 vs 1255 +/- 158 fmoles/mg, p less than 0.01) and 24-week old (2120 +/- 60 vs 1081 +/- 60 fmoles/mg, p less than 0.01) ob/ob mice. In contrast, insulin binding to membrane derived from 24-week old db/db mice was not significantly different from lean controls (1371 +/- 212 vs 1253 +/- 247 fmoles/mg). Insulin-associated tyrosine kinase activity of membranes from ob/ob skeletal muscle was decreased, compared to its normal lean littermate, when compared on a per mg of protein basis in both 12-week (37 +/- 3 vs 21 +/- 3 pmoles/min/mg, p less than 0.05) and 24-week old (71 +/- 5 vs 37 +/- 6 pmoles/min/mg, p less than 0.01) mice. However, no significant differences in kinase activities were observed when the data were normalized and compared on a per fmole of insulin-binding activity basis for the 12-week (12 +/- 1 vs 11 +/- 2) and 24-week (27 +/- 2 vs 20 +/- 3) age groups. Insulin receptor tyrosine kinase activity of db/db skeletal muscle membranes was not different than its normal lean littermate whether expressed on a protein (34 +/- 7 vs 30 +/- 3) or fmole of insulin-binding activity (21 +/- 4 vs 18 +/- 4) basis. These data suggest that insulin receptor tyrosine kinase is not associated with the insulin resistance observed in ob/ob and db/db mice and demonstrate differences in receptor regulation between both animal models.     

Sodium valproate and brainstem energetics

The effect of the anticonvulsant sodium valproate on cerebral brainstem energy metabolism has been investigated. Stupor and coma were produced in mice by the intraperitoneal injection of sodium valproate at a dose of 600 mg/kg. Glucose, glycogen, ATP, and phosphocreatine were measured in small tissue samples from the ascending reticular activating system. Levels of all metabolites were either normal or elevated in precoma and comatose mice as compared to controls. These data are consistent with the concept that sodium valproate does not have a primary action through depletion of high energy phosphates.     

Effect of phenobarbital and thyroxine on hepatocarcinogenesis initiated in mice by nitrosoethylurea and diethylnitrosamine

13-14-day old mice of ICR and CBA strains were given a single intraperitoneal injection of nitrosoethylurea (80 mg/kg) or diethylnitrosamine (50 mg/kg). 2 weeks later, they were given drinking water containing phenobarbital (1 g/L) or thyroxine (2 mg/L). The control mice were given only tap water. 29.4% of male and 42.1% of female ICR mice who had received nitrosoethylurea died of leukemia within 3-6 months after the carcinogen treatment. There was no case of leukemia in mice treated with diethylnitrosamine. Nitrosoethylurea induced 3-more often lung adenomas than diethylnitrosamine. Phenobarbital and thyroxine did not affect development of either leukemias or lung adenomas. By contrast, phenobarbital significantly elevated the number and size of hepatic lesions, whereas thyroxine markedly decreased them in all the experiments. The total and free thyroxine levels were significantly decreased in the blood of mice given phenobarbital and increased in mice given thyroxine. The data obtained indicate that thyroid hormones suppress tumor development in the mouse liver and that the promotion of hepatic tumoro-genesis by phenobarbital is presumably caused by the elimination of this suppressing effect of the thyroid hormones.     

Craniometric measurements of craniofacial malformations in the X-linked hypophosphatemic (Hyp) mouse on two different genetic backgrounds: C57BL/6J and B6C3H.

This study reports data on craniometric measurements in the X-linked hypophosphatemic (Hyp) mouse on two different genetic backgrounds: C57BL/6J and B6C3H. Heads of normal females "+/+," normal males "+/Y," heterozygous mutant females "Hyp/+," and hemizygous mutant males "Hyp/Y" for each genetic background were examined. Data were collected via skull measurements. On a C57BL/6J background, the neurocranium of mutants "Hyp/+" and "Hyp/Y" was shorter and slightly higher than in normal counterparts. On a B6C3H background, mutant mice "Hyp/+" and "Hyp/Y" were shorter in neurocranial length than in normal counterparts. Viscerocranial height was larger in "Hyp/Y" than in normal counterparts. No differences in neurocranial and mandibular height were found. Mutant mice on a C57BL/6J background were compared to mutant mice on a B6C3H background. No differences in neurocranial length were found. Cranial length was shorter in "Hyp/Y" on C57BL/6J than in "Hyp/+" on B6C3H. Facial length parameters were shorter in "Hyp/Y" on C57BL/6J than in "Hyp/Y" and "Hyp/+" mutant mice on B6C3H. Mandibular length was shorter in "Hyp/Y" on C57BL/6J than in "Hyp/+" on C57BL/6J and both mutant mice ("Hyp/Y" and "Hyp/+") on a B6C3H background. The results of this study indicate that craniofacial growth is less affected in mutant mice on a B6C3H genetic background than in mutant mice on a C57BL/6J genetic background.     

不同剂量博莱霉素诱导小鼠肺纤维化的差异及动态变化

目的探讨博来霉素诱导小鼠肺纤维化最佳剂量和方法。方法 126只8周龄雄性ICR小鼠,随机分成一次性大剂量模型和多次小剂量模型。一次性大剂量模型分为200 mg/(kg.bw)BLM组、150 mg/(kg.bw)BLM组、100 mg/(kg.bw)BLM组及阴性对照组(DN组),每组18只,分别经尾静脉一次性注射BLM 200、150、100mg/(kg.bw)及生理盐水10 mL/(kg.bw),各组分别于第7、14、21天各处死6只。多次小剂量模型分为每日10 mg/(kg.bw)BLM组及阴性对照组(N组),分别经尾静脉注射BLM 10 mg/(kg.bw)及生理盐水10 mL/(kg.bw),每天1次,连续注射14 d,两组分别于第14、21、28天各处死6只。留取肺组织,观察肺组织病理改变,检测Ⅲ型胶原的含量,观察小鼠体重及生存率。结果①在一次性大剂量模型中,BLM各剂量组肺泡炎症评分及肺纤维化评分与正常组相比,除100 mg/(kg.bw)BLM组和150 mg/(kg.bw)BLM组在第7天的模型差异无显著性外(P>0.05),其余各组差异均有显著性(P<0.05);各个剂量组Ⅲ型胶原的表达面积与正常组相比,除100 mg/(kg.bw)BLM组在第7天的模型差异无显著性外(P>0.05),其余各组均较正常组高(P<0.05),各个剂量组分别在第21天达到高峰,以200 mg/(kg.bw)BLM组第21天组Ⅲ型胶原的表达面积最高;该模型小鼠各剂量组死亡率为0。②在多次小剂量模型中,各组的肺泡炎症与肺纤维化程度与正常组相比差异均有显著性(P<0.05);各组Ⅲ型胶原的表达也均高于正常组(P<0.05),且随着时间的延长呈进行性增加,在第28天达到高峰;该模型小鼠共死亡11只,死亡率为30.56%。结论在本实验中,以尾静脉一次性注射BLM 200 mg/(kg.bw)后第21天诱导建立的ICR小鼠肺纤维化模型成模最好,其小鼠死亡率低,操作简单,有效安全方便的特点使之有希望成为一种复制肺纤维化的理想模型。     

Cellular glutathione peroxidase protects mice against lethal oxidative stress induced by various doses of diquat

This study was to determine if cellular glutathione peroxidase (GPX1) protects against acute oxidative stress induced by diquat. Lethality and hepatic biochemical indicators in GPX1 knockout mice [GPX1(-/-)] were compared with those of wild-type mice (WT) after an intraperitoneal injection of diquat at 6, 12, 24, or 48 mg/kg of body weight. Although the WT survived all the doses, the GPX1(-/-) survived only 6 mg diquat/kg and were killed by 12, 24, and 48 mg diquat/kg at 52, 4.4 and 3.9 hr, respectively. Compared with those of surviving mice that were sacrificed on Day 7, the dead GPX1(-/-) had diquat dose-dependent increases (P < 0.05) in plasma alanine aminotransferase (ALT) activities. The GPX1(-/-) also had higher (P < 0.05) liver carbonyl contents than those of the WT, but the differences were irrespective of diquat doses. Whereas hepatic total GPX and phospholipid hydroperoxide glutathione peroxidase activities or hepatic GPX1 protein was not significantly affected by the diquat treatment, liver thioredoxin reductase and catalase activities were lower (P < 0.05) in the GPX1(-/-) injected with 12 mg diquat/kg than those of other groups. In conclusion, normal GPX1 expression is necessary to protect mice against the lethality, hepatic protein oxidation, and elevation of plasma ALT activity induced by 12-48 mg diquat/kg.     

Elevated hepatic mitochondrial and peroxisomal oxidative capacities in fed and starved adult obese (ob/ob) mice.

Hepatic mitochondrial and peroxisomal oxidative capacities were studied in young (4-5 weeks old) and adult (6-9 months old) lean and obese ob/ob mice that were fed or starved for 24 or 48 h. The adult obese mice showed elevated capacity for mitochondrial oxidation (ng-atoms of O consumed/min per mg of protein) of lipid and non-lipid substrates, with the exception of pyruvate + malate, and elevated activities of citrate synthase and total carnitine palmitoyltransferase. Oxidative rates and enzyme activities were not affected by starvation of lean or obese mice, and both males and females responded similarly. Peroxisomal palmitoyl-CoA oxidation (nmol/min per mg of peroxisomal protein) was also increased in livers of adult obese mice and did not change with starvation. In young mice, hepatic mitochondrial and peroxisomal oxidative capacities in lean and obese mice were comparable. The increased mitochondrial and peroxisomal oxidative capacities appear to develop with maturation in obese ob/ob mice.     

Production of catechol from benzoate by the wild strain Ralstonia species Ba-0323 and characterization of its catechol 1,2-dioxygenase.

Ralstonia sp. Ba-0323, a wild strain isolated from soil, produced catechol from benzoate and accumulated it outside the cells. The bacterium produced a maximal amount of catechol (1.6 mg/ml) from 3 mg/ml of sodium benzoate in a 20-h growing culture. The conversion rate of benzoate to catechol was 70% on a molar basis. The catechol production by the resting cells increased in the presence of glycerol, and the maximal amount of catechol produced from 3 mg/ml of sodium benzoate reached 1.9 mg/ml at the conversion rate of 83% after 8 h of incubation. Catechol 1,2-dioxygenase, which catalyzed the ring cleavage of catechol, was purified to homogeneity from a cell extract of Ralstonia sp. Ba-0323 growing on benzoate and characterized. The specific activity of the purified enzyme was much lower than those of the dioxygenases from other microorganisms reported. The Km for catechol of the purified enzyme was much higher than those of other dioxygenases. In addition, the NH2-terminal amino acid sequence of the enzyme was less similar to the other catechol 1,2-dioxygenases than they are to each other.     

Circadian differences in behavioral sensitization to cocaine: putative role of arylalkylamine N-acetyltransferase

Circadian rhythms might be involved in addictive behaviors. The pineal secretory product melatonin decreases cocaine sensitization in rats; mice mutant for the critical melatonin-synthesizing enzyme, arylalkylamine N-acetyltransferase (AANAT), exhibit altered behaviors. We hypothesized that AANAT/melatonin system, which is up-regulated at night, affects cocaine sensitization in mice. Intraperitoneal cocaine treatment (10 and 20 mg/kg) dose-dependently increased locomotor activity of both normal (C3H/HeJ) and AANAT mutant (C57BL/6J) mice; this effect was similar during the day and at night. Injections of cocaine during the day for three days resulted in behavioral sensitization in normal and AANAT mutant mice whereas treatment at night triggered sensitization in AANAT-deficient mice only. AANAT expression and synthesis of N-acetylserotonin/melatonin could play a role in addictive properties of cocaine.     

Liver enzyme changes in a guinea-pig model of facial eczema (sporidesmiotoxicosis)

Sporidesmin, a hepatotoxin from Pithomyces chartarum, is responsible for facial eczema in ruminants. In an attempt to clarify the biochemical processes supporting sporidesmin toxicity and response of the liver, haematology, plasma biochemistry and liver enzyme changes were monitored for 21 days in a model for facial eczema resulting from a single intraperitoneal injection of 2.8 mg/kg BW sporidesmin to guinea pigs. Most plasma disturbances were observed 8 days after administration and accounted for starvation, liver cytolysis, and cholestasis or liver enzyme induction. Alterations of hepatic enzyme activities were intense with a maximum increase on days 2 for alkaline phosphatases (ALP) and 8 for gamma-glutamyltransferase (GGT), and a maximum decrease on day 21 for aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). Comparison of liver and plasma enzyme changes indicates that GGT was the most reliable and significant plasma indicator of sporidesmin-associated liver alterations. Moreover, this study points out the validity of the one-dose intoxicated guinea-pig model for research on sporidesmin biochemical toxicity and pathobiology of facial eczema.     

Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice.

Sparse-fur (spf) mutant mice with X-linked ornithine transcarbamylase (OTC) deficiency were examined for hyperammonemia and its effect on energy metabolism. We compared the levels of ammonia, glutamine, glutamate and some of the intermediates of energy metabolism in the brain and liver of spf mice with those of control mice. In spf mice we observed significant increases in ammonia, glutamine, alpha-ketoglutarate and glucose with a significant decrease in ATP, glutamate and pyruvate in both brain and liver. The redox states of the brain and liver were also altered in spf mice. The results suggest that many of the metabolic alterations seen in spf mice could be due to the elevated ammonia levels. The spf mouse may, therefore, be an ideal model for the study of the neurotoxic effects of ammonia in chronic hyperammonemic syndromes.