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PubMedDate not supplied

Ketone body kinetics in vivo using simultaneous administration of acetoacetate and 3-hydroxybutyrate labelled with stable isotopes.

Isotope dilution studies of ketone body (KB) turnover have usually been performed using a single 14C tracer and the so called 'combined KB specific activity'. By definition, this approach does not allow to evaluate the individual kinetics of acetoacetate (AcAc) and 3-hydroxybutyrate (R-BHB) which is feasible only using the separate administration of 14C tracer AcAc and R-BHB. In the present study we followed a different approach using the simultaneous administration in vivo of [1,2,13C2] AcAc and m [1,2,3,4(13)C4] R-BHB which allows to evaluate the individual kinetics of the two KB in the some study, thus minimizing the magnitude of blood sampling and the potential changes in the metabolic conditions of each subject. The four isotopic 13C/12C KB ratios of AcAc and R-BHB tracer and tracee blood concentrations along with the fluorimetric measurement of 12C concentrations were determined in each blood sample. Using compartmental analysis following single dose bolus injection the production rate of KB was 206 +/- 57 mumol/min/1.73 m2 (mean +/- SD). The turnover rate of KB using noncompartmental analysis, during continuous infusion in a separate study was 294 +/- 41. The plasma clearance rates of AcAc and R-BHB were 1966 +/- 502 and 1443 +/- ml/min/1.73 m2, respectively. The mean residence time was 17 +/- 3 min and the total distribution volume 20 +/- 9.7 l/m2. We conclude that: (1) stable isotope tracer infusion allows the contemporary in vivo administration of the two KB and the simultaneous assessment of individual AcAc and R-BHB kinetics; (2) the estimated compartmental and noncompartmental parameters of KB turnover were similar to those observed in normal overnight fasting subjects following separate radioactive tracer injections.

3-Hydroxybutyric Acid↗
PubMed1987

Effect of beta-hydroxybutyrate and acetoacetate on insulin and glucagon secretion from perfused rat pancreas.

To elucidate the physiological significance of ketone bodies on insulin and glucagon secretion, the direct effects of beta-hydroxybutyrate (BOHB) and acetoacetate (AcAc) infusion on insulin and glucagon release from perfused rat pancreas were investigated. The BOHB or AcAc was administered at concentrations of 10, 1, or 0.1 mM for 30 min at 4.0 ml/min. High-concentration infusions of BOHB and AcAc (10 mM) produced significant increases in insulin release in the presence of 4.4 mM glucose, but low-concentration infusions of BOHB and AcAc (1 and 0.1 mM) caused no significant changes in insulin secretion from perfused rat pancreas. BOHB (10, 1, and 0.1 mM) and AcAc (10 and 1 mM) infusion significantly inhibited glucagon secretion from perfused rat pancreas. These results suggest that physiological concentrations of ketone bodies have no direct effect on insulin release but have a direct inhibitory effect on glucagon secretion from perfused rat pancreas.

3-Hydroxybutyric Acid↗
PubMed1982

A simple, rapid method for the determination of glucose, lactate, pyruvate, alanine, 3-hydroxybutyrate and acetoacetate on a single 20-mul blood sample.

Existing methods for the estimation of glucose, lactate, pyruvate, alanine, 3-hydroxybutyrate and acetoacetate normally require relatively large volumes of blood. In addition spectrophotometric methods are tedious and time-consuming. A series of simple methods for the measurement of these metabolites whereby all can be measured on a single 20-microl blood sample is described here. All methods, with the exception of that for glucose, which is measured spectrophotometrically, depend on the use of fluorimetry to determine the concentration of the reduced co-enzyme NADH. As far as is possible, the methods have been standardised for the sake of simplicity and convenience. In routine use they have proved to be both rapid and reliable.

3-Hydroxybutyric Acid↗
PubMed1992

Effects of D-3-hydroxybutyrate and acetoacetate on lactate removal in isolated perfused livers from starved and fed rats.

We examined the influence of nutritional state on the role of the hepatic plasma membrane lactate transporter in determining overall hepatic lactate disposal. The effects of infusion of sodium D-3-hydroxybutyrate (DOHB) on lactate uptake were studied in perfused livers from fed or starved rats. In livers from starved rats, DOHB (15 to 20 mmol/L) inhibited lactate removal by approximately 45%. This effect was associated with a decrease in intracellular lactate concentration, with cell pH remaining unchanged. Inhibition was maximal when perfusate lactate was less than 1.6 mmol/L, and was undetectable at concentrations exceeding 2.5 mmol/L. A similar degree of inhibition was observed with infusion of acetoacetate. These observations add to the evidence that the inhibition of lactate removal by DOHB seen in livers from starved animals is mediated through an effect on the hepatocyte lactate transporter. At similar low levels of perfusate lactate, DOHB infusion produced a decrease in output of lactate from livers obtained from fed animals. When such livers were subjected to prolonged preperfusion, lactate removal, rather than output, was observed; in these livers DOHB stimulated lactate removal, an effect directionally opposite to that observed in livers from starved animals. These data confirm that hepatic lactate transport is a limiting factor for lactate utilization in intact livers from starved rats; in contrast, lactate utilization in livers from fed animals is limited at a step subsequent to plasma membrane transport, ie, possibly pyruvate transport into mitochondria.

3-Hydroxybutyric Acid↗
PubMed1983

Different effects of subcutaneous D,L-3-hydroxybutyrate and acetoacetate injections on food intake in rats.

Cumulative food intake following subcutaneous injection of D,L-3-hydroxybutyrate (DL3HB) or acetoacetate (AcAc) was investigated in rats, because ketone bodies might contribute to food intake regulation according to Kennedy's lipostatic hypothesis. In addition, the metabolic effects of DL3HB-injections were studied by measuring the levels of plasma D3HB, plasma non-esterified fatty acids (NEFA), plasma glycerol, blood glucose, and liver glycogen. Subcutaneously injected DL3HB (10 mmoles/kg body weight) significantly reduced feeding while equimolar AcAc did not. DL3HB-injection increased plasma D3HB and decreased plasma NEFA and plasma glycerol 1-2 hours after the injection but did not affect blood glucose or liver glycogen content. The data suggest that oxidation of D3HB to AcAc contributes to the inhibition of feeding following subcutaneous DL3HB-injection in rats.

3-Hydroxybutyric Acid↗
PubMed2005

In vitro co-metabolism of acetoacetate and ethanol in human hepatic mitochondrial and cytosolic fractions.

The rate of alcohol elimination is highly resistant to acceleration in vivo in well-nourished individuals. The acceleration of ethanol elimination may be achieved by providing the conditions in which the action of alcohol dehydrogenase is not delayed by the insufficiency of the oxidized NAD form. The aim of the study was to verify the theoretically assumed mechanism of accelerating alcohol elimination by administering excessive acetoacetate (Ac-Ac) in the experimental in vitro model. Ac-Ac forming the redox system with beta-hydroxybutyrate (beta-HBA) is the natural acceptor of excessive protons from ethanol oxidation. Ac-Ac and beta-HBA penetrate freely through the cell membranes and are easily assimilated energetic substrates. The examinations were performed using the hepatic homogenates (collected from the cadavers shortly after death) supplemented with ethanol and Ac-Ac. The ethanol levels were determined at 0, 15, 60, 90 and 150 min of the experiment. The findings showed that the equimolar addition of Ac-Ac resulted in a two- to three-fold increase in ethanol oxidation in hepatic homogenates. The biochemical system discussed above resembles the natural way of utilizing the excessive NADH, which is formed during ethanol combustion in chronic alcoholics. The results indicate that further investigations are necessary to assess the clinical importance of this metabolic system.

Acetoacetates↗
PubMed1983

Effect of lactate, pyruvate, acetone, acetoacetate, and beta-hydroxybutyrate on albumin binding of bilirubin.

Lactate, pyruvate, acetone, acetoacetate, and beta-hydroxybutyrate were tested for their bilirubin-displacing effect on human serum albumin. Only lactate had a significant effect at levels found in asphyxiated infants (up to 20 mM). The reserve albumin equivalent for binding bilirubin was determined, using the deputy ligand monoacetyldiaminodiphenyl sulfone (MADDS), in adult human serum albumin solution, neonatal serum, and neonatal albumin solution. Twenty mM lactate caused a 23% decrease of reserve albumin when adult albumin was used, but did not cause any change of binding when neonatal serum or neonatal albumin solution was used. It is unlikely that endogenous substances, acting as competitive ligands, cause the low binding affinity of albumin for bilirubin in sick, premature infants.

3-Hydroxybutyric Acid↗
PubMed2003

Applying the Taguchi robust design to the optimization of the asymmetric reduction of ethyl 4-chloro acetoacetate by bakers' yeast.

This study examined the characteristics and operational parameters of the asymmetric reduction of ethyl 4-chloro acetoacetate by bakers' yeast in order to produce S-4-chloro-3-hydroxybutyric acid ethyl ester. Eight operational variables were also optimized using the Taguchi method with consideration of the freshness of yeast cells as a noise factor. An L(18) orthogonal array was used to design the experiments. The reaction yield and the product's optical purity were considered as two product quality variables. A desirability function was applied to combine these two qualities as a single objective function. Additionally, the signal-to-noise (SN) ratio was used to estimate the variability in product quality. Optimization was undertaken not only to yield the best performance, but also to minimize the variation in quality. The confirmation experiments indicated that the reaction performance and the robustness of the product quality under the optimized conditions were higher than those obtained in other experiments in this study. Our results further demonstrate that the product's optical purity could be increased to >95% by adjusting the operational level of the main factors.

Acetoacetates↗
PubMed2002

Acetoacetate increases expression of intercellular adhesion molecule-1 (ICAM-1) in human brain microvascular endothelial cells.

It has been hypothesized that ketone bodies cause activation of brain endothelial cells and that this is a factor in the intracerebral crises of diabetic ketoacidosis (DKA). In this study we used cultured human brain microvascular endothelial cells (HBMEC) to investigate the effect of beta hydroxybutyrate (BOHB) and acetoacetate (AcAc) on the expression of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1). Increasing concentrations of AcAc, but not BOHB, caused a significant upregulation of ICAM-1 in comparison to unstimulated cells. Glucose concentrations of 10 and 30 mM, but not 50 mM, also resulted in increased expression of ICAM-1. These results support the hypothesis that activation of HBMEC is involved in the acute complications of DKA, and that ketone bodies and hyperglycemia are factors in the perturbed membrane function.

3-Hydroxybutyric Acid↗
PubMed1998

Hyperketonemia (acetoacetate) increases the oxidizability of LDL + VLDL in Type-I diabetic patients.

The reason for the disproportionately higher level of vascular disease in patients with diabetes is not known. Oxidative modification of low-density lipoproteins has been implicated in impaired cholesterol uptake and its deposition in the arterial wall and atherosclerosis. The present study has examined the effects of hyperketonemia, glycemic control and duration of diabetes on the in vitro oxidative susceptibility to Cu++ of low-density lipoprotein (LDL) + very low-density lipoprotein (VLDL) from 34 Type-I diabetic patients without any clinical sign of vascular disease and 22 age-matched normal individuals. LDL + VLDL was isolated from plasma using a micro-affinity column. LDL + VLDL isolated from diabetic patients and age-matched normal individuals was treated with 25 mM CuCl2 for 1.5, 3 and 5 h. The ketone bodies acetoacetate (AA) and beta-hydroxybutyrate (BHB), as well as glycated hemoglobin (HbA1), were measured in the blood by standard methods. There was no difference in the in vitro oxidative susceptibility of LDL + VLDL at all time periods between Type-I diabetics (n = 34) and age-matched normal individuals (n = 22). However, among diabetics, when patients were separated into normoketonemic (NK) and hyperketonemic (HK) groups, in vitro oxidation of LDL + VLDL at 1.5 h from hyperketonemic diabetics was a 69% greater (p < .02) compared with that of normoketonemic diabetics and 80% greater (p < .02) compared with that of normal individuals. There was a significant correlation (r = 0.38, p < .03) between the in vitro oxidation of LDL + VLDL at 1.5 h and AA levels in diabetic patients. The level of in vitro oxidizability of LDL + VLDL did not have any correlation with levels of BHB (r = 0.20, p > .26), HbA1 (r = 0, p > .99), glucose (r = 0.06, p > .75) or duration of diabetes (r = 0.15, p > .40) in diabetic patients. In vitro incubation of normal plasma with AA resulted in an increase in the Cu + induced lipid peroxidation of LDL + VLDL. This study suggests that frequent episodes of ketosis and elevated levels of AA constitute a risk factor for the oxidative modification of low-density lipoproteins and development of vascular disease in diabetic patients.

Acetoacetates↗
PubMed1994

Synthesis of steroid intermediates via alkylation of dianion derived from acetoacetic ester.

A synthetic route for A-ring aromatic steroid intermediates starting from alkylation of dianion derived from acetoacetic ester with m-methoxyphenylethyl bromide to form benzene ring connected to a linear six-carbon fragment is described. This unit, after chemical modifications to 5, was condensed with 2-methylcyclopentan-1,3-dione (6a) to form prochiral trione, 7a, a key synthetic intermediate in A-ring aromatic steroid. Microbial reduction of 7a with Schizosaccharomyces pombe (NRRL Y-164) gave chiral (-)-11 in 65% yield. Starting from 2,2-dimethylsuccinic acid, 2,4,4-trimethylcyclopentan-1,3-dione (6a) was prepared, which was condensed subsequently with 5 to form racemic 7b trione intermediate. Asymmetric cyclization of 7b in the presence of L-(-)-phenylanlanine, followed by acidic cyclization led to regiospecific synthesis of 16,16-dimethyl tetracyclic steroid intermediate.

Acetoacetates↗
PubMedDate not supplied

Acetoacetate and beta-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain microvascular endothelial cells.

Insulin-dependent diabetes mellitus (IDDM), is characterized by a lack of insulin production from beta cells in the pancreas. One of the metabolic consequences of this insulin deficit is an increased hepatic synthesis of ketone bodies, resulting in a serious medical complication, diabetic ketoacidosis (DKA). DKA, in turn, has been associated with the development of cerebral edema. The severity of this complication ranges from death to a subclinical presentation, but seems to be invariably present to some degree. The etiology of the cerebral edema is unknown, but changes in osmolality, pH, and insulin effects on the blood-brain barrier have all been suggested as possible culprits. Blood-brain barrier impermeability is maintained by the endothelial cells (EC) lining the blood vessels. Thus, it would seem likely that alterations in EC function would be necessary for the development of cerebral edema. However, no studies have examined the effects of ketone bodies on brain endothelial cells. The two major ketone bodies in DKA are acetoacetate (AcAc) and beta-hydroxybutyrate (BOHB). In the present study we examined the effect of these ketone bodies on a major intracellular signalling pathway. The changes in intracellular calcium concentration, and the production of two vasoactive peptides, endothelin-1 (ET-1) and vascular permeability factor (VPF/VEGF) in mouse brain microvascular endothelial cells (MBMEC). The present studies demonstrate the BOHB can increase vascular permeability factor. In contrast, AcAc increases the production of the potent vasoconstrictor, endothelin-1. This data would suggest that brain ECs are potential targets of the metabolic alterations in DKA.

3-Hydroxybutyric Acid↗
PubMed2004

Tautomeric equilibrium of ethyl acetoacetate in compressed CO2 + ethanol and CO2 + methanol mixtures.

Tautomerism equilibrium of ethyl acetoacetate (EAA) in compressed CO2 + methanol and CO2 + ethanol mixtures was studied by UV-Vis spectroscopy at 308.15 K and different pressures. The volume expansion coefficient (alpha) of the solvents at different pressures was also determined. The relative permittivity (epsilon) of CO2 + methanol and CO2 + ethanol mixtures at different conditions was calculated using the Kc and Onsager solvent parameter. The equilibrium constant (Kc) of EAA in the binary mixtures increases considerably with increasing pressure or volume expansion coefficient. The relative permittivity or the polarity of the binary mixtures decreases sharply with increasing volume expansion coefficient in the range of 0 < alpha < 1.5. However, as the volume expansion coefficient exceeds 1.5, the relative permittivity decreases slowly. In other words, the dissolution of CO2 in the polar solvents can reduce the polarity of the solvents significantly in the low volume expansion coefficient range, and the polarity of the solution is not sensitive to the volume expansion coefficient as its value is large enough. The difference in polarity of the two solvents reduces with increasing pressure and becomes negligible after volume expansion coefficient exceeds about 2.5.

Acetoacetates↗
PubMed2004

Peroxynitrite-initiated oxidation of acetoacetate and 2-methylacetoacetate esters by oxygen: potential sources of reactive intermediates in keto acidoses.

Oxidative stress is believed to play a role in the pathogenesis of several diseases, including diabetes and inborn errors of metabolism. The types of oxidative damage observed in these pathologies have been attributed to the excessive production of reactive intermediates relating to the accumulation of toxic metabolites. The production of extremely oxidizing peroxynitrite can also be high in these pathologies. We study here the oxidation initiated by peroxynitrite of the ethyl esters of acetoacetate (EAA) and 2-methylacetoacetate (EMAA), metabolites that accumulate in diabetes and isoleucinemia, respectively. Oxygen consumption studies have confirmed that peroxynitrite promotes the aerobic oxidation of EAA and EMAA in phosphate buffer. These reactions were accompanied by ultraweak light emission, which probably arises from triplet carbonyl products formed by thermolysis of dioxetane intermediates. The kinetics of oxygen uptake and chemiluminescence by EAA and EMAA was strongly affected by the phosphate ion, known to catalyze carbonyl enolization and nucleophilic additions to carbonyls. The reaction pH profiles obtained by oxygen consumption and chemiluminescence measurements indicated that the peroxynitrite anion was the initiator of EAA and EMAA aerobic oxidation. EPR spin-trapping studies with the spin traps 3,5-dibromo-4-nitrosobenzenesulfonic acid and 2-methyl-2-nitrosopropane showed the intermediacy of methyl and a carbon-centered radical (*CH2COR) in the oxidation of EAA by peroxynitrite. In the case of EMAA, a tertiary carbon-centered radical (*EMAA) and an acyl radical were detected, the latter probably resulting from the cleavage of a triplet carbonyl product. Superstoichiometric formation of acetate from both substrates confirmed the occurrence of oxygen-dependent chain reactions, here proposed to be initiated by one-electron abstraction from the enolic form of the substrates. The free radicals and electronically excited species generated in the oxidation of EAA and EMAA may help shed further light on the molecular basis of these diseases.

Acetoacetates↗
PubMed1971

Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues.

1. The activities in rat tissues of 3-oxo acid CoA-transferase (the first enzyme involved in acetoacetate utilization) were found to be highest in kidney and heart. In submaxillary and adrenal glands the activities were about one-quarter of those in kidney and heart. In brain it was about one-tenth and was less in lung, spleen, skeletal muscle and epididymal fat. No activity was detectable in liver. 2. The activities of acetoacetyl-CoA thiolase were found roughly to parallel those of the transferase except for liver and adrenal glands. The high activity in the latter two tissues may be explained by additional roles of thiolase, namely, the production of acetyl-CoA from fatty acids. 3. The activities of the two enzymes in tissues of mouse, gerbil, golden hamster, guinea pig and sheep were similar to those of rat tissues. The notable exception was the low activity of the transferase and thiolase in sheep heart and brain. 4. The activities of the transferase in rat tissues did not change appreciably in starvation, alloxan-diabetes or on fat-feeding, where the rates of ketone-body utilization are increased. Thiolase activity increased in kidney and heart on fat-feeding. 5. The activity of 3-hydroxybutyrate dehydrogenase did not change in rat brain during starvation. 6. The factors controlling the rate of ketone-body utilization are discussed. It is concluded that the activities of the relevant enzymes in the adult rat do not control the variations in the rate of ketone-body utilization that occur in starvation or alloxan-diabetes. The controlling factor in these situations is the concentration of the ketone bodies in plasma and tissues.

Acetoacetates↗
PubMed1971

Incorporation of label from D- -hydroxy( 14 C)butyrate and (3- 14 C)acetoacetate into amino acids in rat brain in vivo.

The metabolism of ketone bodies by rat brain was studied in vivo. Rats starved for 48h were given either d-beta-hydroxy[3-(14)C]butyrate or [3-(14)C]acetoacetate by intravenous injection and killed after 3 or 10min. Total radioactivity in the acid-soluble material of the brain and the specific radioactivities of the brain amino acids glutamate, glutamine, aspartate and gamma-aminobutyrate were determined. A group of fed animals were also given d-beta-hydroxy[3-(14)C]butyrate. In the brains of all animals (14)C was present in the acid-soluble material and the specific radioactivity of glutamate was greater than that of glutamine.

Acetoacetates↗
PubMed1977

Effects of acetoacetate administration on glucose metabolism in mammary gland of fed lactating rats.

Administration of acetoactate to fed lactating rats rapidly decreases glucose uptake by the mammary gland, and causes an output of pyruvate, whereas lactate uptake remains unchanged. Similar changes, though not identical, occur in starved lactating rats, which suggests that the increased acetoacetate concentration in this situation may be one of the factors responsible for the alterations in glucose metabolism.

Acetoacetates↗