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PubMed1992

Organic acid profiling in adipocyte differentiation of 3T3-F442A cells: increased production of Krebs cycle acid metabolites.

To try to find special metabolic characteristics of adipose tissue, we examined the organic acids released into the culture medium, which was changed every 48 hours, as 3T3-F442A mouse fibroblasts underwent differentiation to adipocytes under the influence of insulin and fetal calf serum. We identified 13 different organic acids, of which four (malate, fumarate, succinate, and 2-hydroxyglutarate) increased from threefold to 10-fold during an 18-day period of differentiation. After differentiation had occurred, the deletion of insulin from the culture medium resulted in a slight decrease in the concentration of malate, fumarate, and 2-hydroxyglutarate. Other acids were not affected, including 18 that we were unable to identify by gas chromatography-mass spectroscopy. No acid was found to be present only in the medium of either fibroblasts or adipocytes.

3T3 Cells↗
PubMed1992

Staining of argininosuccinate lyase activity in polyacrylamide gel.

A procedure for the direct staining of argininosuccinate lyase activity in polyacrylamide gel is described. The method was based on coupling one of the enzymatic products fumarate with fumarase and malic enzyme catalyzed reactions. Fumarate was first converted to L-malate by fumarase. Malic enzyme then catalyzed the oxidative decarboxylation of L-malate to give CO2 and pyruvate with concomitant reduction of NADP+ to NADPH. Finally the reducing power of NADPH was coupled to phenazine methosulfate and in turn to nitroblue tetrazolium yielding a deeply colored insoluble formazan which may be quantitized or semiquantitized by densitometer.

Animals↗
PubMed1994

Oxidation of NADH by a rotenone and antimycin-sensitive pathway in the mitochondrion of procyclic Trypanosoma brucei brucei.

The pathway of NADH oxidation in the procyclic Trypanosoma brucei brucei was investigated in a crude mitochondrial membrane fraction and in whole cells permeabilized with digitonin. NADH:cytochrome c reductase activity was 75% inhibited by concentrations of antimycin that inhibited 95% succinate:cytochrome c reductase activity suggesting that the major pathway for NADH oxidation in the mitochondria involved the cytochrome bc1 complex of the electron transfer chain. Both NADH:cytochrome c and NADH:ubiquinone reductase activities were inhibited 80-90% by rotenone indicating the presence of a complex I-like NADH dehydrogenase in the mitochondrion of trypanosomes. In whole cells permeabilized with low concentrations of digitonin, the oxidation of malate, proline and glucose (in the presence of salicylhydroxamic acid, the inhibitor of the alternate oxidase) was inhibited 30-50% by rotenone. The presence of an alternative pathway for NADH oxidation involving fumarate reductase was indicated by the observation that malonate, the specific inhibitor of succinate dehydrogenase, inhibited 30-35% the rate of oxygen uptake with malate and glucose as substrates in the digitonin-permeabilized cells. We conclude that in the mitochondrion of the procyclic form of T. brucei, NADH is preferentially oxidized by a rotenone-sensitive NADH:ubiquinone oxidoreductase; however, NADH can also be oxidized to some extent by the enzyme fumarate reductase present in the mitochondrion of T. brucei.

Animals↗
PubMed1994

Differential expression of two succinate dehydrogenase subunit-B genes and a transition in energy metabolism during the development of the parasitic nematode Haemonchus contortus.

The carbohydrate metabolism of free-living and parasitic stages of the sheep nematode Haemonchus contortus was studied, and it was demonstrated that during development a switch occurred from Krebs-cycle activity towards a more fermentative metabolism. During this switch a transition might take place in complex II of the respiratory chain. In the free-living (L3) and early parasitic (XL3) stages, complex II catalyses the oxidation of succinate to fumarate via the Krebs cycle, whereas in adults complex II functions in the reverse reaction, the reduction of fumarate to succinate. L3 and XL3 were shown to already possess a large anaerobic capacity. They survived well in the absence of oxygen or in the presence of cyanide, which completely blocked respiration. Krebs-cycle activity, however, was only partially inhibited by cyanide; the XL3s in particular produced in the presence of cyanide large amounts of propanol, the production of which probably functions as an alternative electron sink. For further investigation of the observed metabolic switch, complex II of the respiratory chain, a key enzyme involved in this switch, was studied. The B subunit of complex II was cloned and sequenced. These clones all showed sequences similar to the B subunit of succinate dehydrogenase from other species, and included the amino-terminal signal sequence for importation into mitochondria. Two genes were identified, types 1 and 2, based on the DNA and amino acid sequences and on the lack of cross-reaction to each other when used as probes on Southern blots. On Northern blots, the two genes showed a different expression pattern during the development of the parasite.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin.

Iron supplementation is required by most dialysis patients receiving recombinant human erythropoietin. The efficacy of oral iron is variable in these patients, and many require the use of intravenous iron dextran to maintain adequate iron levels, defined as transferrin saturation greater than 20%, serum ferritin greater than 100 ng/mL, and serum iron greater than 80 micrograms/dL. To determine the efficacy of different oral iron preparations in maintenance of iron status, we prospectively studied 46 recombinant human erythropoietin-treated patients and randomized them to receive different oral iron preparations. These four preparations included Chromagen (ferrous fumarate; Savage Laboratories, Melville, NY), Feosol (ferrous sulfate; SmithKline Beecham, Inc, Pittsburgh, PA), Niferex (polysaccharide; Central Pharmaceuticals, Inc, Seymour, IN), or Tabron (ferrous fumarate; Parke-Davis, Morris Plains, NJ). All patients were prescribed approximately 200 mg of elemental iron daily of their assigned iron preparation with at least 100 mg ascorbic acid daily for 6 months. At baseline and bimonthly during the study, serum iron, transferrin saturation, ferritin, hematocrit, and recombinant human erythropoietin dose were monitored; in addition, compliance and side effects were recorded by patient interview. All patients were able to maintain target hematocrit during the 6 months of study. However, there were differences in the trends of serum iron, percent transferrin saturation, and ferritin when considered singly or in combination between the four groups of iron medications. The percent of laboratory values measured over the study period in each group that met the criteria of transferrin saturation more than 20% was greatest in the Tabron group (58%), followed by the Feosol (47%), Chromagen (33%), and Niferex (31%) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Competition for electron transfer between cytochromes P450scc and P45011 beta in rat adrenal mitochondria.

Rat adrenal mitochondria contain approximately equal levels of P450scc and P45011 beta, each reduced by NADPH through adrenodoxin reductase (ADX-reductase) and adrenodoxin (ADX). Constitutive cholesterol side-chain cleavage (SCC) can be increased over 20-fold through a combination of hormonal activation and inhibition of cholesterol metabolism in vivo prior to isolation of the mitochondria. This stimulation, which results from accumulated reactive cholesterol, does not significantly affect either the dependence of activities on the concentration of isocitrate (IC) and succinate (SU) or the ratio of maximum activities [3:1] supported by these reductants. Thus, the rate of cholesterol SCC is determined independently by electron transfer and the amount of reactive cholesterol. Hydroxylation of deoxycorticosterone (11 beta and 18 positions) required much higher levels of each reductant, indicating less effective reductant transfer to P45011 beta. Reactions at P450scc and P45011 beta, mediated by IC, are enhanced by low concentrations of various dicarboxylates anions (fumarate, SU). The actions of SU dehydrogenase inhibitors and the activity of fumarate, a poor direct reductant, suggest that higher production of NADPH results from malate-enhanced uptake of isocitrate. Only synergistic combinations of reductants are sufficient to sustain maximum rates of 11-deoxycorticosterone (DOC) metabolism, whereas IC is fully effective for P450scc. Increased reaction at P450scc (cholesterol loading or addition of 20 alpha-hydroxycholesterol) decreased simultaneous DOC metabolism at P45011 beta in inverse proportion to the estimated intramitochondrial generation of NADPH (1 mM or 10 mM SU > 1 mM IC > 10 mM IC). These decreases were reversed by inhibition of P450scc. Crossover inhibition caused by maximum DOC metabolism was less pronounced. EGTA/albumin treatment, which enhanced activities at both P450scc and P45011 beta, presumably via increased NADPH, diminished this cross-competition. The differential dependence on reductants and the characteristics of crossover competition are consistent with a roughly three-fold more favorable partitioning of electron transfer to P450scc, possibly caused by preferential interaction of reduced adrenodoxin with P450scc.

Adrenal Cortex↗
PubMed1982

Mitochondrial NADH oxidase activity of adult Hymenolepis diminuta (Cestoda).

1. Mitochondria from adult Hymenolepis diminuta displayed a membrane-associated, rotenone-sensitive NADH oxidase and NADH-dependent fumarate reductase system. 2. Both the H. diminuta oxidase and fumarate reductase were relatively insensitive to antimycin A. potassium cyanide and sodium azide, at concentrations which significantly inhibited the NADH oxidase system of rat liver. 3. Malonate effectively depressed the mitochondrial NADH oxidase activity of both H. diminuta and adult Ascaris suum (Nematoda). 4. An involvement of Mn2+ ion, in NADH utilization by the H. diminuta oxidase, was apparent. 5. The utilization of NAD(P)H by H. diminuta, mitochondrial membranes resulted in hydrogen peroxide formation. Succinate utilization also resulted in peroxide accumulation but at a much slower rate than that found for NAD(P)H.

Animals↗
PubMed1990

Molybdenum cofactor negative mutants of Escherichia coli use citrate anaerobically.

Anaerobically, Escherichia coli cannot grow using either glycerol or citrate as sole carbon and energy source. However, it has been reported that a mixture of glycerol and citrate will support growth. We have found that wild-type strains of E. coli K-12 do not grow on glycerol plus citrate anaerobically. However, growth eventually occurs due to the frequent appearance of mutants. We found that such Cit+ mutants were defective in anaerobic respiration with nitrate or trimethylamine-N-oxide and were chlorate resistant (i.e. molybdenum cofactor deficient). Conversely, well characterized mutants in any of chlA, B, D, E, G and N were also able to use citrate anaerobically. No anaerobic growth differences between wild type and chl mutants were observed either with fermentable sugars or with glycerol plus fumarate or glycerol plus tartrate. Citrate lyase was induced anaerobically by citrate and repressed by glucose in both wild type strains and chl mutants. Furthermore, levels of citrate lyase, fumarate reductase, malate dehydrogenase, fumarase and alcohol dehydrogenase were similar in both types of strains under anaerobic conditions. It is conceivable that a functioning molybdenum cofactor prevents use of citrate by keeping citrate lyase in the inactive form.

Aconitate Hydratase↗
PubMed1995

Kinetics of substrate oxidation by whole cells and cell membranes of Helicobacter pylori.

Oxygen uptake by Helicobacter pylori cells and membranes was determined. Cells from stirred broth cultures or agar plates, suspended in buffer, possessed a variable and apparently endogenous respiration which could be sustained for several hours. In contrast, oxygen consumption by cells from statically incubated broth cultures, in the absence of added substrate, was transient or undetectable. These latter cells, however, oxidised ethanol, fumarate, glucose, D-lactate, pyruvate and succinate, though glucose-oxidising ability declined rapidly. The Kms for D-lactate, pyruvate and succinate metabolism were low (< or = 20 microM) and oxygen uptake was approximately 1.5, 2 and 2 mol per mol substrate respectively, indicating metabolism beyond acetate plus CO2 and implying the presence of tricarboxylic acid cycle activity. Cell membranes oxidised fumarate, D-lactate, NADH, NADPH and succinate. NADPH oxidation was six times more rapid than that of NADH. Rates of oxygen uptake by cells suspended in buffer with metabolisable substrate were < 20% of those for cells suspended in a brain heart infusion medium. Uninoculated medium consumed significant quantities of oxygen.

Cell Membrane↗
PubMed1996

Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study.

OBJECTIVES: Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter. BACKGROUND: Ibutilide fumarate is an investigational class III antiarrhythmic agent that prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current. It can be administered intravenously and has a rapid onset of electrophysiologic effects. METHODS: The efficacy and safety of ibutilide were studied in 200 patients with atrial flutter > 3 h in duration or atrial fibrillation 3 h to 90 days in duration. Patients were randomized to receive a single intravenous dose of placebo or an infusion of ibutilide fumarate at 0.005, 0.010, 0.015 or 0.025 mg/kg body weight over 10 min. Conversion was defined as termination of the atrial arrhythmia during or within 60 min after infusion. Forty-one patients received placebo and 159 received ibutilide (0.005 mg/kg [n = 41], 0.010 mg/kg [n = 40], 0.015 mg/kg [n = 38] or 0.025 mg/kg [n = 40]). RESULTS: The arrhythmia terminated in 34% of drug-treated patients. The rates of successful arrhythmia termination were 3% for placebo and 12%, 33%, 45% and 46%, respectively, for 0.005-, 0.010-, 0.015- and 0.025-mg/kg ibutilide. The placebo and 0.005-mg/kg ibutilide groups had lower success rates than all other dose groups (p < 0.05). The mean time to termination of the arrhythmia was 19 min (range 3 to 70) from the start of infusion. Successful arrhythmia termination was not affected by enlarged left atrial diameter, decreased ejection fraction, presence of valvular heart disease or the use of concomitant medications (beta-adrenergic blocking agents, calcium channel blocking agents or digoxin). Arrhythmia termination was not predicted by the magnitude of corrected QT interval prolongation but was associated with a shorter duration of atrial arrhythmia. The most frequent adverse events in ibutilide-treated patients were sustained and nonsustained polymorphic ventricular tachycardia (3.6%). All patients with sustained polymorphic ventricular tachycardia were successfully treated with direct current cardioversion and had no recurrence. The occurrence of proarrhythmia did not correlate with ibutilide plasma concentration. CONCLUSIONS: These data demonstrate that ibutilide is able to rapidly terminate atrial fibrillation and atrial flutter.

Aged↗
PubMed2004

High-performance liquid chromatography-based methods of enzymatic analysis: electron transport chain activity in mitochondria from human skeletal muscle.

This study addresses an application of pyridine nucleotide enzymatic analyses to evaluate the activity of the mitochondrial electron transport chain (reduced nicotinamide adenine dinucleotide (NADH) oxidase) and Complexes I and II in samples of human muscle as small as approximately 10 mg wet weight. Key aspects in this adaptation are the use of high-performance liquid chromatography with fluorescence detection of NADH and use of alamethicin, a channel-forming antibiotic that enables an unrestricted access of substrates into the mitochondrial matrix. The procedure includes disintegration of tissue by Polytron homogenizer, extraction of myosin from myofibrillar fragments by KCl/pyrophosphate to facilitate release of mitochondria, and preparation of fractions of subsarcolemmal and intermyofibrillar mitochondria. Oxidation of NADH or succinate is assayed in the presence of 40 microg/ml alamethicin and the reaction is terminated by H(2)SO(4), which also destroys the remaining NADH. Nicotinamide adenine dinucleotide (NAD) or fumarate concentrations are measured using alcohol dehydrogenase or fumarase plus malic dehydrogenase reactions, respectively. Generation of NADH, assessed in auxiliary reactions in the presence of hydrazine, is strictly proportional to NAD or fumarate content across a concentration range of 1-20 microM. NADH is quantitatively analyzed with a detection limit of 3-5 pmol by HPLC using a reverse-phase Hypersil ODS column connected to a fluorescence detector.

Alamethicin↗
PubMed2005

Physiological role of rhodoquinone in Euglena gracilis mitochondria.

Rhodoquinone (RQ) participates in fumarate reduction under anaerobiosis in some bacteria and some primitive eukaryotes. Euglena gracilis, a facultative anaerobic protist, also possesses significant rhodoquinone-9 (RQ9) content. Growth under low oxygen concentration induced a decrease in cytochromes and ubiquinone-9 (UQ9) content, while RQ9 and fumarate reductase (FR) activity increased. However, in cells cultured under aerobic conditions, a relatively high RQ9 content was also attained together with significant FR activity. In addition, RQ9 purified from E. gracilis mitochondria was able to trigger the activities of cytochrome bc1 complex, bc1-like alternative component and alternative oxidase, although with lower efficiency (higher Km, lower Vm) than UQ9. Moreover, purified E. gracilis mitochondrial NAD+-independent D-lactate dehydrogenase (D-iLDH) showed preference for RQ9 as electron acceptor, whereas L-iLDH and succinate dehydrogenase preferred UQ9. These results indicated a physiological role for RQ9 under aerobiosis and microaerophilia in E. gracilis mitochondria, in which RQ9 mediates electron transfer between D-iLDH and other respiratory chain components, including FR.

Aerobiosis↗
PubMed2005

Alteration of substrate specificity of aspartase by directed evolution.

Aspartase (l-aspartate ammonia-lyase, EC 4.3.1.1), which catalyzes the reversible deamination of l-aspartic acid to yield fumaric acid and ammonia, is highly selective towards l-aspartic acid. We screened for enzyme variants with altered substrate specificity by a directed evolution method. Random mutagenesis was performed on an Escherichia coli aspartase gene (aspA) by error-prone PCR to construct a mutant library. The mutant library was introduced to E. coli and the transformants were screened for production of fumaric acid-mono amide from l-aspartic acid-alpha-amide. Through the screening, one mutant, MA2100, catalyzing deamination of l-aspartic acid-alpha-amide was achieved. Gene analysis of the MA2100 mutant indicated that the mutated enzyme had a K327N mutation. The characteristics of the mutated enzyme were examined. The optimum pH values for the l-aspartic acid and l-aspartic acid-alpha-amide of the mutated enzyme were pH 8.5 and 6.0, respectively. The K(m) value and V(max) value for the l-aspartic acid of the mutated enzyme were 28.3 mM and 0.26 U/mg, respectively. The K(m) value and V(max) value for the l-aspartic acid-alpha-amide of the mutated enzyme were 1450 mM and 0.47 U/mg, respectively. This is the first report describing the alteration of the substrate specificity of aspartase, an industrially important enzyme.

Aspartate Ammonia-Lyase↗
PubMed2006

Effects of tributyltin on the energy metabolism of pen shell (Atrina pectinata japonica).

We examined the effects of tributyltin (TBT) on aerobic and anaerobic energy metabolism of pen shell (Atrina pectinata japonica). We exposed pen shells to TBT at nominal concentrations of 0 (control) and 1.0microg/l for 72h under aerobic condition. At the end of the exposure, half of the pen shells in each treatment were wrapped in plastic wrap to simulate exposure to hypoxia and held at 25 degrees C for another 12h. The concentrations of the products of energy metabolism, namely lactate, pyruvate, fumarate and succinate, in adductor muscle were measured. The exposure to TBT under aerobic condition significantly elevated lactate, pyruvate and fumarate concentrations (p<0.001). After subsequent exposure to anaerobic condition, the mean concentration of succinate in the TBT treatment group was 64% of that in the control group, but there were no significant differences. Our results suggest that the energy metabolism of pen shell is disrupted by exposure to TBT.

Aerobiosis↗
PubMed2006

Nonezymatic formation of succinate in mitochondria under oxidative stress.

The products of the reactions of mitochondrial 2-oxo acids with hydrogen peroxide and tert-butyl hydroperoxide (tert-BuOOH) were studied in a chemical system and in rat liver mitochondria. It was found by HPLC that the decarboxylation of alpha-ketoglutarate (KGL), pyruvate (PYR), and oxaloacetate (OA) by both oxidants results in the formation of succinate, acetate, and malonate, respectively. The two latter products do not metabolize in rat liver mitochondria, whereas succinate is actively oxidized, and its nonenzymatic formation from KGL may shunt the tricarboxylic acid (TCA) cycle upon inactivation of alpha-ketoglutarate dehydrogenase (KGDH) under oxidative stress, which is inherent in many diseases and aging. The occurrence of nonenzymatic oxidation of KGL in mitochondria was established by an increase in the CO(2) and succinate levels in the presence of the oxidants and inhibitors of enzymatic oxidation. H(2)O(2) and menadione as an inductor of reactive oxygen species (ROS) caused the formation of CO(2) in the presence of sodium azide and the production of succinate, fumarate, and malate in the presence of rotenone. These substrates were also formed from KGL when mitochondria were incubated with tert-BuOOH at concentrations that completely inhibit KGDH. The nonenzymatic oxidation of KGL can support the TCA cycle under oxidative stress, provided that KGL is supplied via transamination. This is supported by the finding that the strong oxidant such as tert-BuOOH did not impair respiration and its sensitivity to the transaminase inhibitor aminooxyacetate when glutamate and malate were used as substrates. The appearance of two products, KGL and fumarate, also favors the involvement of transamination. Thus, upon oxidative stress, nonenzymatic decarboxylation of KGL and transamination switch the TCA cycle to the formation and oxidation of succinate.

Amination↗
PubMed2006

Metabolomic discrimination of different grades of pine-mushroom (Tricholoma matsutake Sing.) using 1H NMR spectrometry and multivariate data analysis.

Metabolomic analysis of raw and cooked pine-mushrooms (Tricholoma matsutake Sing.) of different grades was performed using (1)H nuclear magnetic resonance (NMR) spectrometry and principal component analysis (PCA). PCA of the (1)H NMR spectra of aqueous fractions allowed different grades of raw pine-mushroom to be discriminated by a combination of principal component (PC) 1 and PC 2, which accounted cumulatively for 94.1% of the variation in all variables. The major peaks in the (1)H NMR spectra that contributed to discrimination of raw mushrooms were assigned to choline, trehalose, threonine, leucine/isoleucine, succinic acid, alanine, and fumaric acid. The combination of PC 1 (70.8%) and PC 3 (7.5%) allowed different grades of cooked pine-mushroom to be discriminated, and the major peaks in the (1)H NMR spectra that contributed to discrimination of cooked mushrooms were assigned to succinic acid, trehalose, and fumaric acid. This metabolomic analysis-based method allows different grades of pine-mushroom to be distinguished without any prepurification.

Agaricales↗
PubMed2006

Cloning, expression, purification, and characterization of Leishmania major dihydroorotate dehydrogenase.

Leishmania major Friedlin (LmjF) is a protozoan parasite whose genomic sequence has been recently elucidated. Here we have cloned, overexpressed, purified, and characterized the product of the gene from LmjF chromosome 16: LmjF16.0530, which encodes a protein with putative dihydroorotate dehydrogenase activity. Dihydroorotate dehydrogenase (DHODH) is a flavoprotein that catalyses the oxidation of L-dihydroorotate to orotate, the fourth sequential step in the de novo pyrimidine nucleotide synthesis pathway. The predicted enzyme from L. major was cloned and expressed in Escherichia coli strain BL21(DE3) as a histidine-tag fusion protein and purified to homogeneity using affinity chromatography. The final product was homogeneous in SDS-PAGE gel electrophoresis. The dihydroorotate oxidase activity has been assayed and the steady-state kinetic mechanism has been determined using fumarate as the oxidizing substrate. The catalysis by LmDHODH enzyme proceeds by a Ping-Pong Bi-Bi mechanism and the kinetic parameters Km were calculated to be 90 and 418 microM for dihydroorotate and fumarate, respectively, and Vmax was calculated to be 11 micromol min-1 mg-1. Our results confirmed that the product of the gene LmjF16.0530, whose function has previously been predicted based on homology to known proteins, can therefore be positively assigned as L. major DHODH.

Animals↗
PubMed2003

On the association of succinate dehydrogenase mutations with hereditary paraganglioma.

Hereditary paraganglioma (PGL) is characterized by the development of slow-growing, highly vascularized tumors that can present either as hormonally silent head and neck tumors or as abdominal pheochromocytomas. PGL tumors are caused by germline inactivating heterozygous mutations in the SDHB, SDHC and SDHD genes, which encode three of the four subunits of succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase; mitochondrial complex II). Here, potential mechanisms by which SDH mutations could lead to tumor development are discussed. Mechanisms that lead to variations in the prevalence, penetrance and expressivity of SDH subunit mutations remain to be clarified to improve the clinical management of PGL patients. Recently, germline mutations in the FH gene, the product of which (fumarate hydratase) catalyzes the conversion of fumarate to malate in the Krebs cycle, have been detected in a distinct hereditary tumor syndrome, which is characterized by uterine and skin leiomyomatosis and papillary renal cancer. Although the exact mechanisms of tumorigenesis in both disorders are unknown, SDH and FH could be involved in the control of cell proliferation under normal physiological conditions in the affected tissue types. Whereas SDH might be involved in hypoxic proliferation of paraganglia, FH might play an important role in the regulation of ammonium metabolism in smooth muscle cells.

Animals↗