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PubMed1996

Growth hormone, insulin-like growth factor-I and lipid metabolism: interactions with sex steroids.

Steroid hormones usually act via specific receptors and the hormone-receptor complex then influences the transcription of genes. These effects are often permissive for the actions of peptide hormones such as insulin and growth hormone (GH). The best known effects are those of cortisol. Since cortisol is always present, the sex steroids often modify cortisol effects. In adipose tissue, lipoprotein lipase (LPL), in the presence of insulin, is expressed via a glucocorticoid receptor, increasing transcription and stabilizing the enzyme. This process is efficiently inhibited by GH via posttranslational effects, and lipolysis is markedly stimulated. Testosterone inhibits LPL expression and, in the presence of GH, markedly increases lipolysis via multiple interactions along the lipolytic cascade. In human adipose tissue, direct effects of estrogen and progesterone cannot be demonstrated, probably because of the apparent absence of specific receptors. These hormones presumably via indirect mechanisms, perhaps by interaction with other hormone receptors.

Female↗

PubMed1991

Metabolic interaction and disposition of methyl ethyl ketone and m-xylene in rats at single and repeated inhalation exposures.

1. Rats were exposed to m-xylene (300 ppm) and methyl ethyl ketone (MEK, 600 ppm) vapour, separately and in combination. 2. Repeated exposures to m-xylene enhanced liver drug-metabolizing capacity, whereas MEK showed no effects. After mixed exposure the cytochrome P-450-dependent monooxygenase activities were additively or synergistically induced. 3. In the presence of MEK the overall metabolism of xylene was strongly inhibited both after single and repeated exposures, an effect accompanied by elevation of xylene concentration in blood (18-29%) and fat (25-32%). 4. The 24-h excretion of the urine metabolites of m-xylene was decreased by 22-24% in mixed exposures: the excretion of methylhippuric acid was decreased (29%), but that of 2,4-dimethylphenol increased (9-35%). 5. After repeated inhalation exposures the excretion of xylene metabolites in urine was consistently higher, whereas the concentrations of xylene in fat (but not the concentration of MEK) were lower than after a single treatment, conceivably due to accelerated metabolic clearance of xylene. 6. Thioether excretion in urine was enhanced in xylene-treated rats (7-13-fold), but was not influenced by the induced changes in the metabolism of xylene. Xylene inhalation caused liver GSH to decrease slightly (10%), as did inhalation of MEK, but the latter did not enhance the excretion of thioethers. 7. MEK is a potent inhibitor of the side-chain oxidation of m-xylene producing methylhippuric acid, but not of its ring oxidation to 2,4-dimethylphenol, and exhibits a synergistic inducing effect on liver enzymes responsible for the oxidation of m-xylene. The increased ring oxidation of m-xylene was not associated with increased production of reactive metabolites indicated by GSH-depletion or thioether formation.

Administration, Inhalation↗

PubMed1981

Metabolic interactions between opiates and alcohol.

1. Acute preperfusion with ethanol does not alter significantly the initial hepatic extraction or subcellular distribution of narcotics, or the immediate biotransformation of the long-acting narcotic, methadone, using the isolated perfused rabbit liver. However, the acute administration of ethanol may alter distribution and/or impair hepatic drug metabolism in perfusion studies of longer duration, or in vivo, as has been suggested by others in studies of several drugs. 2. Following chronic treatment with both ethanol and methadone in the rat, plasma levels of unmetabolized methadone, determined by gas liquid chromatography, are significantly lowered. 3. Following chronic treatment with methadone alone, blood elimination rates of ethanol are accelerated to a greater extent than following chronic treatment with ethanol alone in the rat; following chronic treatment with both methadone and ethanol, rates of ethanol elimination are accelerated to a significantly more rapid rate than following treatment with either agent alone. 4. To date, clinical studies in patients on chronic steady-dose methadone maintenance treatment, without liver disease, polydrug abuse, or heavy use of ethanol, show no significant acute dispositional interactions between methadone and ethanol. 5. Clinical studies in patients on chronic steady-dose methadone maintenance treatment, without liver disease, polydrug abuse, or heavy use of ethanol, show no significant dispositional interactions between methadone and disulfiram (Antabuse) when the latter was given for one week for study purposes only. 6. Clinical studies of possible dispositional interactions between methadone and ethanol in methadone-maintained patients, who are also chronic abusers of alcohol, are now in progress.

Alcoholism↗

PubMed2003

The role of cholesterol in pathogenesis of Alzheimer's disease: dual metabolic interaction between amyloid beta-protein and cholesterol.

The implication that cholesterol plays an essential role in the pathogenesis of Alzheimer's disease (AD) is based on the 1993 finding that the presence of apolipoprotein E (apoE) allele epsilon;4 is a strong risk factor for developing AD. Since apoE is a regulator of lipid metabolism, it is reasonable to assume that lipids such as cholesterol are involved in the pathogenesis of AD. Recent epidemiological and biochemical studies have strengthened this assumption by demonstrating the association between cholesterol and AD, and by proving that the cellular cholesterol level regulates synthesis of amyloid beta-protein (Abeta). Yet several studies have demonstrated that oligomeric Abeta affects the cellular cholesterol level, which in turn has a variety of effects on AD related pathologies, including modulation of tau phosphorylation, synapse formation and maintenance of its function, and the neurodegenerative process. All these findings suggest that the involvement of cholesterol in the pathogenesis of AD is dualistic-it is involved in Abeta generation and in the amyloid cascade, leading to disruption of synaptic plasticity, promotion of tau phosphorylation, and eventual neurodegeneration. This review article describes recent findings that may lead to the development of a strategy for AD prevention by decreasing the cellular cholesterol level, and also focuses on the impact of Abeta on cholesterol metabolism in AD and mild cognitive impairment (MCI), which may result in promotion of the amyloid cascade at later stages of the AD process.

Alzheimer Disease↗

PubMed1977

Alcohols-histones metabolic interactions in intact human erythrocytes.

Alcohols have a stimulating effect on the intracellular peroxidatic reactions of intact human erythrocytes. This effect depends directly on the molecular weight of alcohol and the H2O2 concentration. The human leukocyte nuclear histones, flavin-adenine-dinucleotide (FAD) and nicotinamide-adenine-dinucleotide (NAD) inhibit the peroxidatic reactions during the metabolism of alcohols in intact human erythrocytes. The participation of erythrocyte catalase, the possible metabolic pathway and the inhibitory effect of human leukocyte nuclear histones, FAD and NAD on the intracellular metabolism of alcohols is discussed.

Alcohols↗

PubMed1982

Metabolic interaction between m-xylene and ethanol.

Ingestion of a moderate dose of ethanol (0.8 g/kg) by volunteers prior to 4-h inhalation exposure to m-xylene (6.0 or 11.5 mmol/m3) caused marked alterations in xylene kinetics. After ethanol intake the blood xylene level rose about 1.5-2.0-fold and urinary methylhippuric acid excretion declined by about 50% suggesting that ethanol decreased the metabolic clearance of xylene by about one half during xylene inhalation. This effect was noticeable up until a few hours after completed xylene exposure. Urinary excretion of 2,4-xylenol, the minor m-xylene metabolite, was generally not decreased by ethanol and sometimes the reverse seemed to be the case. The disturbance of xylene kinetics can be hypothesized to be caused mainly by ethanol-mediated inhibition of microsomal metabolism. When four volunteers who ingested ethanol prior to m-xylene inhalation at the higher concentration were monitored for blood acetaldehyde, transiently raised levels were found without notable effects on ethanol elimination. This observation may explain why some individuals experienced dizziness and nausea during the combined ethanol-xylene exposure.

Acetaldehyde↗

PubMed2002

Species differences in the metabolism of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid in vitro: implications for prediction of metabolic interactions in vivo.

1. Mouse studies have indicated that the antitumour effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are dramatically potentiated in combination with other drugs, and it has been proposed that optimization of the therapeutic potential of DMXAA would exploit combination therapy. The aim was to identify the most appropriate animal model for further investigations of the pharmacokinetics of possible DMXAA-drug combinations and their extrapolation to patients. 2. Qualitatively, the metabolic profile for DMXAA in liver microsomes was similar in mouse, rat, rabbit and humans, with glucuronidation and 6-methylhydroxylation the two major metabolic pathways. In all species, the intrinsic clearance by glucuronidation was at least 2-fold that due to hydroxylation. There was significant variability in the in vitro kinetic parameters (Km, Vmax), with the mouse being the least efficient DMXAA metabolizer compared with the other species. 3. Mouse, rat and rabbit renal microsomes exhibited DMXAA glucuronidation activity, but only the rabbit showed 6-methylhydroxylation. For the total in vitro CL(int) (Vmax/Km) by glucuronidation and 6-methylhydroxylation, the ratio of kidney:liver was 0.67, 0.03 and 0.34 in the mouse, rat and rabbit respectively. However, taking into account the liver and kidney weight difference, it is apparent that the in vivo renal metabolism would not be a major contributor to the overall elimination of DMXAA. 4. The inhibitory profile for liver DMXAA glucuronidation was similar across species, but there was remarkable interspecies variability in the inhibition of liver DMXAA 6methylhydroxylation. 5. Extrapolation of in vitro intrinsic clearance to in vivo gave a significant underestimation of plasma clearance for all species. However, there was a significant allometric relationship for plasma clearance and volume of distribution, but not for maximum tolerated dose across species. 6. The results indicate that animal models may have a limited role in the extrapolation to patients of drug interactions with agents such as DMXAA that have immunomodulating activity that may vary widely between species.

Animals↗

PubMed1981

[Metabolic interactions of promethazine (author's transl)].

Owing to enzyme induction, the pretreatment of female Wistar rats with promethazine (Prothazin, Atosil) produces a shortening of the hexobarbital sleeping time, a slight increase in the relative liver weight, an increase in the N-demethylation of aminophenazone, the O-demethylation of codeine phosphate, the O-demethylation of p-nitroanisol, the glucuronidation of p-nitrophenol and the NADPH-cytochrome c reductase activity in the 9.000 g supernatant of liver homogenates. Particularly striking are the strong stimulation of the N-demethylation and the also potentiated [in contrast to the findings obtained with dioxopromethazine (Prothanon)] UDP-glucuronyltransferase activity, whereas the cytochrome P-450 concentration shows a slight trend toward increase, but this is not statistically significant. The findings obtained justify the expectation of drug interactions in case of repeated application of promethazine in the framework of a combined therapy.

Animals↗

PubMed1987

Role of receptors in metabolic interaction of histamine with human vascular endothelial cells and skin fibroblasts. An ordered sequence of enzyme action.

The interaction of histamine with an H1 receptor on human endothelial cells evokes production of the lipid mediator prostaglandin I2 (PGI2) and is accompanied by tachyphylaxis of this H1 receptor response (Baenziger, N. L., Fogerty, F. J., Mertz, L. F., and Chernuta, L. F. (1981) Cell 24, 915-923). We have explored the affected cells' capability for subsequent metabolic degradation of histamine molecules. Human vascular endothelial cells and skin fibroblasts exhibit a two-stage histamine degradation sequence whose participants are an enzyme native to the cells themselves and one provided from an extracellular source. Initially, the cells' endogenous histamine N-methyltransferase activity mediates conversion of cell-associated [3H]histamine to tele-methylhistamine with retention of this intermediate metabolite. Subsequently, in the presence of exogenous diamine oxidase derived from fetal calf serum or human placenta, cell-associated tele-methyl-histamine is further converted to the end product methylimidazoleacetic acid. After an initial lag phase lasting 3-6 min, the cell-associated radioactivity accumulates as methylimidazoleacetic acid at a linear rate substantially enhanced over that without diamine oxidase. The entire sequence is blocked by the histamine methyltransferase inhibitor homodimaprit. Accumulation of [3H]histamine metabolites by endothelial cells is saturable both with respect to exogenous diamine oxidase and to histamine. Thus this metabolic pathway is carried out at the level of the individual cell by means of binding sites or receptors for the substrate and for the distal degradative enzyme, diamine oxidase.

Amine Oxidase (Copper-Containing)↗

PubMed1986

[Metabolic interaction between cimetidine, ranitidine and amitriptyline/chlordiazepoxide].

The effects of cimetidine and ranitidine on plasma levels of amitriptyline and chlordiazepoxide were examined in a biphasic study with 12 young male volunteers. During the first phase all subjects received a fixed combination of 2 X amitriptyline (25 mg) and chlordiazepoxide (10 mg) daily for one week. After the last dose blood samples were drawn up to 72 hours in order to detect plasma levels of the drugs and their main metabolites. Following a wash-out-period of 7 days two groups of 6 subjects, each were formed in a randomized order. In addition to the mentioned medication 3 X 200 mg plus 1 X 400 mg of cimetidine daily or 2 X 150 mg of ranitidine daily were administered for one week. After discontinuation of amitriptyline/chlordiazepoxide the medication with H2-blockers was kept and blood samples were collected again for plasma analysis. Plasma level detections were carried out employing HPLC. The change of the area under the plasma level-time curve (AUC), total clearance and terminal half-life served as parameters indicating interaction. Under treatment with cimetidine plasma levels of amitriptyline and chlordiazepoxide were significantly (5%) increased, whereas such effects could not be observed with ranitidine. Due to these interactions under the conditions of coadministration of H2-blockers and amitriptyline and/or chlordiazepoxide the use of ranitidine is recommended.

Adult↗

PubMed1997

Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes.

AIMS: Nine antimalarial (plus two metabolites of proguanil) and twelve non-antimalarial drugs were tested for their possible interaction with CYP3A4-catalysed 3-hydroxylation of quinine by human liver microsomes in vitro. METHODS: 3-Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective IC50 values were estimated for the twenty-one drugs and two metabolites of proguanil tested herein. RESULTS: Thirteen drugs exhibited an inhibitory effect on the 3-hydroxylation of quinine. According to the respective mean IC50 values, the inhibitory rank order of the drugs was: ketoconazole > troleandomycin (TAO, with preincubation) > doxycycline > omeprazole > primaquine > tetracycline = TAO (without preincubation) > nifedipine > erythromycin > verapamil > cimetidine > diltiazem > oleandomycin > hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean IC50 > 200 or 500 microM). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3-hydroxylation with a mean IC50 value of 17 microM, followed by primaquine and tetracycline, with mean IC50 values of 20 and 29 microM, respectively. CONCLUSIONS: When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co-administrated with quinine.

Anti-Infective Agents↗

PubMed1981

Ionic and possible metabolic interactions between sensory neurones and glial cells in the retina of the honeybee drone.

This is a review paper that includes original calculations and figures. The drone retina is composed of two essentially uniform populations of cells, the photoreceptors and the glial cells. The photoreceptors contain many mitochondria but no glycogen has been detected; the glial cells contain much glycogen and very few mitochondria. The oxygen consumption of the photoreceptors in the dark is 20 microliters min-1 per g of retinal tissue and in response to a single flash of light there is an extra consumption that reaches a maximum of 40 microliters min-1 per g. In addition, light stimulation of the photoreceptors leads to changes in the glycogen metabolism of the glial cells, and to movements of K+. Measurements with intracellular K+-sensitive micro-electrodes showed that during light stimulation with a series of flashes the K+ activity (alpha K) in the photoreceptors fell by an average of 27% while in the glial cells alpha K rose by an amount that is estimated to correspond to most of the quantity of K+ lost by the photoreceptors. The relative contributions to the clearance of extracellular K+ of extracellular diffusion, spatial buffering and possible net K+ uptake by glial cells are discussed.

Animals↗

PubMed2006

Transgenomic metabolic interactions in a mouse disease model: interactions of Trichinella spiralis infection with dietary Lactobacillus paracasei supplementation.

Irritable Bowel Syndrome (IBS) is a common multifactorial intestinal disorder for which the aetiology remains largely undefined. Here, we have used a Trichinella spiralis (T. spiralis)-induced model of post-infective IBS, and the effects of probiotic bacteria on gut dysfunction have been investigated using a metabonomic strategy. A total of 44 mice were divided into four groups: an uninfected control group and three T. spiralis-infected groups, one as infected control and the two other groups subsequently treated with either Lactobacillus paracasei (L. paracasei) NCC2461 in spent culture medium (SCM) or with L. paracasei-free SCM. Plasma, jejunal wall and longitudinal myenteric muscle samples were collected at day 21 post-infection. An NMR-based metabonomic approach characterized that the plasma metabolic profile of T. spiralis-infected mice showed an increased energy metabolism (lactate, citrate, alanine), fat mobilization (acetoacetate, 3-D-hydroxybutyrate, lipoproteins) and a disruption of amino acid metabolism due to increased protein breakdown, which were related to the intestinal hypercontractility. Increased levels of taurine, creatine and glycerophosphorylcholine in the jejunal muscles were associated with the muscular hypertrophy and disrupted jejunal functions. L. paracasei treatment normalized the muscular activity and the disturbed energy metabolism as evidenced by decreased glycogenesis and elevated lipid breakdown in comparison with untreated T. spiralis-infected mice. Changes in the levels of plasma metabolites (glutamine, lysine, methionine) that might relate to a modulation of immunological responses were also observed in the presence of the probiotic treatment. The work presented here suggests that probiotics may be beneficial in patients with IBS.

Amino Acids↗

PubMed1982

Metabolic interactions of aldehyde dehydrogenase with therapeutic and toxic agents.

The specific physiological roles of ALDH have not been determined. In this overview, we have identified malondialdehyde as one potential endogenous toxic aldehyde that is oxidized by ALDH. Undoubtedly, there are other cytotoxic aldehydes which occur in several different tissues that are detoxified by this same system of enzymes. Intuitively, the role of aldehyde dehydrogenases in the detoxification of xenobiotic aldehydes should also receive additional consideration and attention. An interesting feature of specific studies described in this overview is that a single aldehydic substrate, like malondialdehyde, may be a substrate for one ALDH isozyme and a potent inhibitor of ALDH present in another cellular compartment. Assuming that the ALDH susceptible to this inhibition performs other important physiological or biochemical functions, a potentiating effect would occur. Thus, the efficient metabolism of potentially cytotoxic aldehydes may be a protective mechanism against a number of different organ system pathologies. Another striking feature of ALDH is its sensitivity to in vitro and in vivo inhibition by a number of chemically and pharmacologically diverse agents. This characteristic suggests that ALDH may be a target enzyme for inhibition by several therapeutically important drugs or their metabolites. As a result, the perturbation of ALDH by specific therapeutic agents suggests a potential role of this enzyme in a number of different drug-induced toxicities.

Alcohol Oxidoreductases↗

PubMed1992

Intracellular pH regulation and metabolic interactions in hepatic tissues.

Intracellular pH (pHi) regulation in the vertebrate liver relies heavily on ionic transport mechanisms. Liver, in common with many tissues, has plasma membrane Na(+)-H+ and Cl(-)-HCO3- electroneutral exchangers which work in opposition to tightly control pHi. Mammalian livers also possess electrogenic Na(+)-HCO3- exchangers, capable of base uptake, which, when coupled to pHi-mediated changes in membrane potential, probably confer an additional measure of pHi control, compared to fish livers, where the transporter appears to be functionally absent. It is suggested that this may be a fundamental difference between aquatic and aerial breathing. pHi regulation has barely been examined in invertebrate hepatic tissues, but already some interesting differences are apparent. Notably, an electrogenic 2Na(+)-1H+ acid-extrusion system is present in apical membranes of crustacean hepatopancreas. Despite these ionic control systems, complex acid-base disturbances (e.g., "metabolic" acidosis) have been known for some time to influence hepatic metabolism in vertebrates, but few studies have carefully examined the independent effects of the acid-base variables involved. Thus mechanistic explanations for the effects of acid-base disturbances are scarce. Ureogenesis in mammals has been well studied, and several pH-related mechanisms are evident. In contrast, the pH-insensitivity of ureogenesis in fish liver may represent a second difference between aquatic and terrestrial species. In summary, by virtue of its metabolic diversity, liver represents a potentially important organ in acid-base balance, and an interesting study tissue for interrelationships between metabolism and acid-base balance.

Acid-Base Equilibrium↗

PubMed1996

In-vitro metabolic interaction of bunitrolol enantiomers in rabbit liver microsomes.

We have examined the 4-hydroxylation of bunitrolol in rabbit and rat liver microsomes. Significant species differences (rabbit < rat of both sexes) and sex (male > female of both species) were observed in the formation of 4-hydroxybunitrolol from racemic bunitrolol (10 microM). The 4-hydroxylation of bunitrolol racemate and enantiomers showed biphasic kinetics, a low-Km system and a high-Km system, in liver microsomes from rabbits of both sexes. There were significant differences in Km and Vmax values [(+) > (-)] for 4-hydroxylations of (+)-bunitrolol and (-)-bunitrolol in the low-K(m) system. Furthermore, the rate of clearance (Vmax/Km) was 20- to 200-fold for the low-Km system compared with the high-Km system, indicating that enzymes in the low-Km system play a major part in the rabbit liver microsomal bunitrolol metabolism. Inhibition studies using cytochrome P450 inhibitors such as quinidine, quinine, and alpha-naphthoflavone or polyclonal antibodies raised against rat P450-2D and -1A enzymes did not make clear which P450 enzymes are involved in bunitrolol 4-hydroxylation in rabbit liver microsomes. The 4-hydroxylase activity of (+)-bunitrolol was slightly higher than that of (-)-bunitrolol in separated incubations containing male rabbit liver microsomes and an enantiomer concentration of 10 microM. However, the 4-hydroxylation of (+)-bunitrolol (10 microM) was markedly suppressed in the presence of its antipode (10 microM), whereas (-)-bunitrolol 4-hydroxylation was not affected by the presence of its antipode, resulting in a change of the stereoselectivity from (+) > (-) for enantiomer to (+) < (-) for racemate. The difference in the Michaelis constants in the low-Km system, where the Km value of (-)-bunitrolol is one-eighth that of (+)-bunitrolol, is thought to cause the change in the stereoselectivity in rabbit liver microsome-mediated bunitrolol 4-hydroxylation.

Adrenergic beta-Antagonists↗

PubMed1990

Nonspecific and metabolic interactions between steroid hormones and human plasma lipoproteins.

Previous observations demonstrated that steroid hormones associate with plasma lipoproteins. The objective of this study was to estimate the relative importance of lipoproteins as steroid hormone binding agents in comparison to sex hormone binding globulin, corticosteroid binding globulin, and albumin in both normal and hyperlipidemic human plasma. The 16 steroid hormones and related metabolites included in the study were: androstanediol, androstenediol, androstenedione, androsterone, corticosterone, cortisol, dehydroepiandrosterone, deoxycorticosterone, dihydrotestosterone, estradiol, estriol, estrone, 17 alpha-hydroxyprogesterone, pregnenolone, progesterone, and testosterone. The binding activity of these 16 steroid hormones with purified high density lipoprotein (HDL), low density lipoprotein and very low density lipoprotein were separately evaluated by equilibrium dialysis incubations to yield 48 steroid hormone-lipoprotein combinations for further study. In incubations with HDL, six steroid hormones (androstenediol, dehydroepiandrosterone, dihydrotestosterone, estradiol, pregnenolone, and progesterone) were identified as non-equilibrium, apparently due to metabolic conversion of the steroid hormones. The metabolic activity for the three delta 5-3 beta hydroxy steroids and estradiol appears to be fatty acid esterification by lecithin:cholesterol acyltransferase. The computer program TRANSPORT, which was used to evaluate only the nonspecific steroid hormone-lipoprotein association levels in a 16 x 6 matrix at simultaneous equilibrium, indicated that lipoprotein-bound steroid hormones ranged from 1% for cortisol to 56% for pregnenolone in normal human blood. Simulated projections of the increase in nonspecific steroid hormone association with lipoproteins during hyperlipidemia are also presented. These results demonstrate how lipoproteins are likely to be important in the transport and metabolism of steroid hormones in human plasma.

Carrier Proteins↗

PubMed1975

Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis.

1. The infusion of sodium dichloroacetate into rats with severe diabetic ketoacidosis over 4h caused a 2mM decrease in blood glucose, and small falls in blood lactate and pyruvate concentrations. Similar findings had been reported in normal rats (Blackshear et al., 1974). In contrast there was a marked decrease in blood ketone-body concentration in the diabetic ketoacidotic rats after dichloroacetate treatment. 2. The infusion of insulin alone rapidly decreased blood glucose and ketone bodies, but caused an increase in blood lactate and pyruvate. 3. Dichloroacetate did not affect the response to insulin of blood glucose and ketone bodies, but abolished the increase of lactate and pyruvate seen after insulin infusion. 4. Neither insulin nor dichloroacetate stimulated glucose disappearance after functional hepatectomy, but both agents decreased the accumulation in blood of lactate, pyruvate and alanine. 5. Dichloroacetate inhibited 3-hydroxybutyrate uptake by the extra-splachnic tissues; insulin reversed this effect. Ketone-body production must have decreased, as hepatic ketone-body content was unchanged by dicholoracetate yet blood concentrations decreased. 6. It was concluded that: (a) dichloroacetate had qualitatively similar effects on glucose metabolism in severely ketotic rats to those observed in non-diabetic starved animals; (b) insulin and dichloroacetate both separately and together, decreased the net release of lactate, pyruvate and alanine from the extra-splachnic tissues, possibly through a similar mechanism; (c) insulin reversed the inhibition of 3-hydroxybutyrate uptake caused by dichloroacetate; (d) dichloroacetate inhibited ketone-body production in severe ketoacidosis.

Acetates↗