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Results for “Metabolic interaction”

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PubMed1999

Reorganized cerebral metabolic interactions in temporal lobe epilepsy.

Patients with left temporal lobe epilepsy demonstrate language impairments that are not well understood. To explore abnormal patterns of brain functional connections with respect to language processing, we applied a principal component analysis to resting regional cerebral metabolic data obtained with positron emission tomography in patients with right- and left-sided temporal lobe epilepsy and controls. Two principal components were expressed differentially among the groups. One principal component comprised a pattern of metabolic interactions involving left inferior frontal and left superior temporal regions-corresponding to Broca's and Wernicke's areas, respectively-and right mesial temporal cortex and right thalamus. Functional couplings between these brain regions were abnormally enhanced in the left-sided epilepsy patients. The right thalamic left superior temporal coupling was also abnormally enhanced in the right-sided epilepsy patients, but differentially from that in the left-sided patients. The other principal component was characterized by a pattern of metabolic interactions involving right and left mid prefrontal and right superior temporal cortex. Although both the right- and left-sided epilepsy patients showed decreased functional couplings between left mid prefrontal and the other brain regions, a weaker right-left mid prefrontal coupling in the left-sided epilepsy patients best distinguished them from the right-sided patients. The two mutually independent, abnormal metabolic patterns each predicted verbal intelligence deficits in the patients. The findings suggest a site-dependent reorganization of two independent, language-subserving pathways in temporal lobe epilepsy.

Adolescent↗

PubMed2003

Metabolic interactions between low doses of benzo[a]pyrene and tributyltin in arctic charr (Salvelinus alpinus): a long-term in vivo study.

We have previously reported that short-term, single exposure to a high dose of tributyltin (TBT), a widely used antifouling biocide, inhibited both the in vivo metabolism and metabolic activation of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) in fish; (BaP), in turn, stimulated TBT metabolism. Here, we provide further mechanistic evidence of mutual metabolic interactions between BaP and TBT in response to long-term, repeated exposures to low doses. Juvenile Arctic charr (Salvelinus alpinus) received 10 separate i.p. injections (a single injection every 6 days) of BaP (3 mg/kg), TBT (0.3 mg/kg), or both in combination; control fish received corn oil vehicle only. Two days after the 2nd (Day 8), 6th (Day 32), and 10th dose (Day 56), blood, bile, and liver samples were collected and analyzed for a suite of biomarkers. HPLC/fluorescence analysis indicated that TBT cotreatment inhibited the formation of (+)-anti-BaP diol-epoxide adducts with plasma albumin (53%, Day 8), hepatic DNA (27%, Day 32), or both albumin and globin (50 and 58%, Day 56) compared to BaP alone. This antagonistic interaction was associated with a time-dependent modulation (inhibition at Day 8, enhancement at Day 32) of both cytochrome P450 (P450)1A-mediated ethoxyresorufin O-deethylase (EROD) activity and biliary BaP metabolite formation. TBT cotreatment also inhibited (39%) the BaP-mediated induction of hepatic glutathione S-transferase (GST) activity observed at Day 8. Treatment with TBT alone increased EROD activity (60%) at Day 32, but decreased both GST activity (70 and 37%) and glutathione content (24% and 16%) at Days 32 and 56, respectively. GC/MS analysis revealed that, at Day 56, BaP cotreatment increased (200%) the levels of biliary butyltin compounds, including mono- and dibutyltin metabolites. This potentiative interaction was associated with a protective effect of BaP cotreatment against the TBT-mediated decreases in GST activity and glutathione content. The current results demonstrate that, whereas TBT inhibited BaP bioactivation via a time-dependent modulation of P4501A induction, BaP stimulated the Phase II metabolism of TBT and/or its biliary excretion. The mutual metabolic interactions between these two widespread aquatic pollutants reinforce the need for long-term in vivo interactive studies at low doses.

Albumins↗

PubMedDate not supplied

Metabolic interaction between morphine and naloxone in human liver. A common pathway of glucuronidation?

Metabolic interaction between naloxone and morphine has been studied in vitro in human liver microsomes. Morphine and naloxone are metabolized by an UDP-glucuronyl transferase to their 3-glucuronides. There is a very good correlation between the rates of formation of morphine-3-glucuronide and of naloxone-3-glucuronide. Naloxone seems to have a 10-fold higher affinity for the enzyme binding site than does morphine. Morphine and naloxone show bisubstrate kinetic patterns which appear very similar.

Chromatography, High Pressure Liquid↗

PubMed1999

In vitro metabolic interaction studies: experience of the Food and Drug Administration.

A total of 194 new molecular entities approved by the Food and Drug Administration between 1992 and 1997 were surveyed to determine the role of in vitro metabolic interactions in the conduct of drug-drug interaction studies and to examine the methods used in these studies. Approximately 30% of the submissions were found to have in vitro metabolism-based interaction studies, most of which were inhibitory in nature. Chemical inhibition was the most commonly used approach in studying drug interactions in vitro. In this article, an attempt to assess the quality of the chemical inhibition approach was made. Four areas were found to be often overlooked: (1) incubation time and concentrations of the drug, (2) the difference between inhibition constant (k(i)) and 50% inhibitory concentration (IC50) values, (3) the substrate-dependent inhibition potential, and (4) the metabolic genotype or phenotype of the liver donor. We discuss the pitfalls in estimating drug interactions when these four areas are overlooked.

Cytochrome P-450 Enzyme Inhibitors↗

PubMed1995

Brain, liver and blood distribution kinetics of carbamazepine and its metabolic interaction with clomipramine in rats: a quantitative microdialysis study.

The aim of this work was to study the transport across the blood-brain barrier (BBB), blood and liver distribution kinetics, metabolic interaction and local liver metabolism of carbamazepine (CBZ) in the rat, using microdialysis with the internal standard technique as in vivo calibration method. CBZ and its major metabolite, carbamazepine-10,11-epoxide (CBZ-EPO), are homogenously distributed to hippocampus and cerebellum. The ratios of the areas under the concentration-time curve (AUC) for both brain regions to blood AUC were not different from unity for CBZ; they were 0.46 +/- 0.08 (hippocampus) and 0.45 +/- 0.05 (cerebellum) for CBZ-EPO. In addition, the disposition of CBZ and CBZ-EPO in blood and liver, after a single dose of CBZ, was studied in control animals and in rats after pretreatment with clomipramine (CLOMI). A 2-fold increase in the blood AUC of CBZ and a decrease to 33% of the blood AUC of CBZ-EPO in the pretreated group demonstrate the metabolic inhibition of CBZ-EPO formation by clomipramine. The ratios of the AUCCBZ-EPO to the AUCCBZ, as a measure of CBZ-EPO formation, were not different for blood and liver within the control and the clomipramine-pretreated groups, but the ratios were significantly lower for liver and blood in the clomipramine group compared with the control animals. In addition, CBZ was administered locally in the extracellular fluid of the liver via the microdialysis probe. The liver metabolic ratio, expressed as the ratio of the formed CBZ-EPO concentration to the CBZ concentration administered, ranged from 18.2 +/- 1.2% to 19.6 +/- 1.6%.

Animals↗

PubMed1976

Metabolic interaction of secondary amines and tertiary amino propiophenones with monoamine oxidase systems.

The metabolic interaction of three secondary amines and three nitrogen-containing metabolites of safrole (tertiary amino propiophenones) with rat liver mitochondrial monoamine oxidase systems was studied in vitro employing [7-14C] benzylamine--HCl as a substrate. The two cyclic secondary amines, piperidine and pyrrolidine, showed hyperbolic competitive inhibition while pure competitive inhibition was observed in case of dimethylamine--HCl and three safrole metabolites. Inhibition characteristics for rat liver, kidney and brain mitochondrial monoamine oxidase with two cyclic secondary amines and tertiary amino with two cyclic secondary amines and tertiary amino propiophenones of safrole and elemicin were investigated manometrically using tyramine and serotonin as the substrates.

Animals↗

PubMed1979

Acute metabolic interaction of ethanol and drugs.

Addition of ethanol in vitro was found to inhibit the microsomal metabolism of a variety of drugs such as meprobamate, aminopyrine, pentobarbital and zoxazolamine. In all cases, a mixed type of inhibition was obtained. When the concentration of alcohols of different chain lengths required to inhibit 50% of the metabolism of drugs was plotted against their corresponding octanol-water partition coefficients (Po/w) it was found that the inhibitory potency of alcohols is linearly related to the partition coefficients, with a slope of 0.98. In vivo acute administration of ethanol also resulted in decreased whole body metabolism of meprobamate, aminopyrine, pentobarbital, zoxazolamine and aniline. In vitro addition of pentobarbital, phenobarbital and meprobamate had no significant effect on ethanol metabolism by liver slices. Acute pretreatment with these drugs also had no effect on the rate of ethanol metabolism in vivo as measured in the whole body or as estimated from the rate of decrease of blood ethanol concentration. It appears therefore that acute metabolic interaction of ethanol and drugs is a one sided phenomenon, i.e. ethanol inhibits drug metabolism, whereas drugs do not inhibit ethanol metabolism. Ethanol inhibition of drug metabolism in vitro appears to result from a modification of the lipophilic milieu that surrounds the cytochrome P-450 in the microsomal membrane. Interference with the hydrophobic sites may either directly or indirectly affect the catalytic activities of the microsomal enzyme.

Animals↗

PubMedDate not supplied

Comutagenesis-IV in vitro metabolism of the comutagen 2-amino-3-methylpyridine: species differences and metabolic interaction with norharman.

The metabolism of 2-amino-3-methylpyridine (2A3MP) in vitro has been investigated using the rat, rabbit, dog, marmoset, guinea pig and hamster hepatic microsomes and S9 supernatants (10,000 g fraction). Species differences were observed in the in vitro formation of 2-amino-3-methylpyridine-N-oxide (2A3MPNO), 2-amino-3-hydroxymethylpyridine (2A3HMP) and 2-amino-3-methyl-5-hydroxypyridine (2A3M5HP). The order of activity for 2A3MPNO using hepatic microsomes was dog > rat > rabbit > guinea pig > marmoset > hamster, for 2A3HMP dog > hamster > guinea pig > rat > rabbit > marmoset, for 2A3M5HP rabbit > hamster > dog > rat > guinea pig > marmoset. When hepatic S9 supernatants from various uninduced species were used, rabbit was more active for the production of 2A3MPNO and 2A3M5HP whilst hamster was more effective for the formation of 2A3HMP. Pretreatment of rats with arochlor 1254 enhanced the formation of all metabolites. No species produced a metabolite having the properties of 2-hydroxylamino-3-methylpyridine or further oxidation or condensation products. The present study did not show the presence of any new metabolite after co-incubation of 2A3MP with norharman.

Aminopyridines↗

PubMed2025

Health-associated key gut microbiota drives the variation in community metabolic interactions in non-human primates.

Gut microbiota often undergo metabolic cross-feeding and resource competition. However, our understanding of global variations in these interactions and their implications for host health remain elusive. By analyzing a microbial genome catalog from 841 fecal metagenomes across 53 primate species worldwide, we identified key microbiota assigned to two taxa, i.e., Bacillota_A and Pseudomonadota, which well predicted the trade-off of community-level interaction types between metabolic competition and cooperation. Specifically, Bacillota_A species were inherently competitive and amino acid auxotrophic and typically found in anaerobic habitats. In contrast, members of Pseudomonadota were inherently cooperative, siderophore producers, and more abundant in aerobic conditions. Random forest models successfully distinguished unhealthy gut samples from healthy samples through the key competitive and cooperative microbiota, suggesting potential links between community metabolic interactions and host health. Together, this study enhances our mechanistic understanding of microbial interaction dynamism within complex gut ecosystems, offering new targets for understanding host health.

Animals↗

PubMed1975

Metabolic interactions of glucose, acetoacetate and adrenaline in rat submaxillary gland in vitro.

1. The metabolic interactions between glucose, acetoacetate and adrenaline were studied in submaxillary-gland slices. 2. Acetoacetate (2.5 mM) inhibited glucose removal by 22% and entry of glucose carbon into the tricarboxylic acid cycle by 54%. 3. Acetoacetate caused an increase in (glucose 6-phosphate) together with an increase in (citrate), a finding that suggests that the phosphofructokinase step might be inhibited by the elevated (citrate). Support for this suggestion was obtained in experiments in which fluoracetate was used to elevate (citrate). 4. A further site of action of acetoacetate at the pyruvate dehydrogenase step was suggested by an increase in the lactate+pyruvate pool, and the finding that pyruvate removal and (3-14C)pyruvate oxidation were inhibited by acetoacetate. 5. Adrenaline, a stimulator of secretion by this tissue, increased glucose removal by 25%. Adrenaline increased glucose removal to the same extent when acetoacetate was also present in the incubation medium. In both cases the increase was accompanied by a fall in (glucose 6-phosphate). 6. Adrenaline also overcame the inhibition of pyruvate removal caused by acetoacetate. 7. The tissue (ATP) decreased by about 50% on addition of adrenaline, and a similar fall was observed in vivo after adrenergic stimulation by isoproterenol. 8. Omission of Ca-2+ from the medium prevented the fall in (glucose 6-phosphate) and (ATP) caused by adrenaline, although adrenaline was still able to stimulate glucose removal. The inhibitory effect of acetoacetate on gluocse removal was reversed by adrenaline, but there was no stimulation above the control rates. Inhibition of pyruvate removal by acetoacetate was not overcome by adrenaline in the absence of Ca-2+. 9. Dibutyryl cyclic AMP had no effect on glucose removal or on (ATP). 10. Possible mechanisms by which adrenaline can bring about its metabolic effects are discussed.

Acetoacetates↗

PubMed2005

SINGLE NUCLEOTIDE POLYMORPHISMS THAT INFLUENCE LIPID METABOLISM: Interaction with Dietary Factors.

Cardiovascular disease (CVD) risk is the result of complex interactions between genetic and environmental factors. During the past few decades, much attention has focused on plasma lipoproteins as CVD risk factors. The current evidence supports the concept that gene-environment interactions modulate plasma lipid concentrations and potentially CVD risk. The findings from studies examining gene-diet interactions and lipid metabolism have been highly promising. Several loci (i.e., APOA1, APOA4, APOE, and LIPC) are providing proof-of-concept for the potential application of genetics in the context of personalized nutritional recommendations for CVD prevention. However, the incorporation of these findings to the clinical environment is not ready for prime time. There is a compelling need for replication using a higher level of scientific evidence. Moreover, we need to evolve from the simple scenarios examined nowadays (i.e., one single dietary component, single nucleotide polymorphism, and risk factor) to more realistic situations involving interactions between multiple genes, dietary components, and risk factors. In summary, there is need for both large population studies and well-standardized intervention studies.

Biological Transport↗

PubMed1971

Erythrocyte metabolism: interaction with oxygen transport.

Studies of the interactions between the metabolism and the function of the red cell have shown the importance of the red cell's metabolism in contributing to the maintenance of adequate oxygen delivery. Some of the phosphorylated intermediates of glycolysis, especially DPG, are now known to reduce the affinity of hemoglobin for oxygen. Current evidence indicates that this phenomenon is due to the effects of the binding of DPG to the , beta-chains of deoxyhemoglobin. It appears that increases in red cell concentrations of DPG commonly occur during hypoxia, and that these increases (as well as normal physiological variation) significantly enhance oxygen transport. Artificial manipulation of erythrocyte metabolism may soon prove to be of great clinical usefulness in the treatment of a great variety of disorders which limit oxygen transport.

Adenosine Triphosphate↗

PubMed2000

Possible metabolic interaction between hexane and other solvents co-exposed at sub-occupational exposure limit levels.

OBJECTIVE: To investigate whether metabolic interactions exist between hexane (HEX) and other solvents when co-exposed at the levels below occupational exposure limits. METHODS: Workers, 219 men in ten workshops in total, volunteered to participate in the study. They were occupationally exposed to mixtures of HEX and one or more of toluene (TOL), ethyl acetate (EA) and acetone (ACE). Time-weighted average intensity of vapor exposures was monitored by diffusive personal sampling. 'Free'- and 'total'-2,5-hexanedione (HD) levels in the end-of-shift urine samples were determined by gas chromatography (GC) before and after acid hydrolysis of urine, respectively, and expressed as observed (HDob) or after correction for creatinine concentration (HDcr) or urine specific gravity (HDsg). Possible interaction was examined by multiple regression analysis (MRA), taking either free- or total-HD as a dependent variable, and the four solvent concentrations as independent variables. RESULTS: In most cases, exposure intensity did not exceed the current occupational exposure limits even when additiveness was assumed. In addition that HEX was the most influential independent variable in all cases as expected, the MRA showed that, in cases of free-HD, ACE was also influential to HDob although weakly, but not to HDcr or HDsg. With regard to total-HD, ACE was weakly influential to HDob and HDsg, and EA also weakly to HDcr. The effect of ACE on free- or total-HD was not detected, however, when 22 men exposed only to HEX and ACE were subjected to the same analysis. Similarly, the effect of EA on total-HD was not observed among the remaining 197 men exposed to HEX, TOL and EA only. CONCLUSIONS: When the exposures were below occupational exposure limits, the free-HD levels in urine after HEX exposure will not be modified by co-exposures to TOL, EA or ACE.

Acetates↗

PubMed1991

Behavioral and metabolic interaction between gossypol and ethanol.

The effects of gossypol on ethanol-elicited responses pertaining to liver ethanol, acetaldehyde-metabolizing enzymes and alcohol preference were studied in rodents. Intraperitoneal injection of a single dose of gossypol, 100 mg/kg, inhibited hepatic alcohol dehydrogenase for 50 h in mice from both sexes. The acute gossypol treatment produced earlier inhibition of mouse liver cytoplasmic aldehyde dehydrogenase in male than female mice. Acute gossypol administration initially inhibited mouse liver subcellular mitochondrial aldehyde dehydrogenase in both sexes which was not evident 50 h later. Administration of gossypol, 10 mg/kg i.p., to male rats with preference for ethanol caused aversion for ethanol drinking. The enzymatic determinations indicate gender sensitivity of subcellular mouse liver aldehyde dehydrogenase to gossypol. The behavioral study suggests adverse metabolic interaction between gossypol and alcohol which may underlie the rat aversion to voluntary ethanol drinking.

Alcohol Dehydrogenase↗

PubMed1998

Intercellular Transport-metabolic interactions in the nervous tissue developing under conditions of afferentation deficit (transplants in the anterior eye chamber).

Intercellular transport-metabolic interactions were investigated at the ultrastructural level in the grafts of the embryonic rat hippocampus and septum developing for 3 to 12 months in the anterior eye chamber of adult rats. The signs of highly increased transport from the blood capillaries ingrowing from the host's iris into the grafts (multiple pinocytotic vesicles in the endothelium and pericytes) were observed. The glial cells, which were accumulated at the graft surface, had pinocytotic invaginations and microvilli, which indicated their possible participation in the active transport of metabolites from the surrounding intraocular fluid. An increased level of direct communications, manifested in pinocytoses and large gap junctions between apposed nerve and glial cells was also present within the grafts. Moreover, microphagocytosis, as internalization of surface membrane fragments with adjacent cytoplasm of the neighbouring structure (including dendrites and axons), was often observed in the grafted tissue. It is suggested that the observed communications between neuronal and glial cells may participate in both trophic and functional interactions. An increase in the level of nonsynaptic interactions in the grafted nervous tissue may be regarded as a manifestation of the compensatory adaptation to the absence of normal tissue surrounding afferent connections and efferent targets.

Animals↗

PubMed2005

Characterization of the metabolic interaction between trihalomethanes and chloroacetic acids using rat liver microsomes.

The aim of this study was to investigate the in vitro metabolism of trihalomethanes (THMs) in the presence of trichloroacetic acid (TCA), dichloracetic acid (DCA), monochloroacetic acid (MCA), and 4-methylpyrazole (4-MP) using liver microsomes from male Sprague-Dawley rats. Using the vial equilibration technique, initial experiments were carried out with starting concentrations of approximately 40 ppm THMs and 12-22 mM chloroacetic acids. The results indicated a mutual metabolic inhibition between THMs present as binary or quaternary mixtures. Although DCA and MCA had no influence on THMs, TCA produced a marked inhibition of the metabolism of all THMs: chloroform (CHCl3) (55%), bromodichloromethane (BDCM) (34%), dibromochloromethane (DBCM) (30%), and bromoform (TBM) (23%). The presence of 4-MP also reduced THM metabolism, the importance of which decreased in the following order: CHCl3 > BDCM > DBCM = TBM. In further vial equilibration experiments, using 9-140 ppm as starting concentrations of THMs, enzyme kinetic parameters (i.e., Michaelis constant, K(m), and maximum velocity, V(max)) were determined both in the absence and in the presence of TCA (12.2 mM). Results are consistent with a competitive inhibition between TCA and CHCl3, whereas the metabolic inhibition of BDCM and TMB by TCA was non-competitive. As for DBCM, results suggest a more complex pattern of inhibition. These results suggest that CYP2E1 is involved in the metabolism of THMs as well as in the metabolic interaction between THMs and TCA.

Acetates↗

PubMed1989

[Electron microscopic research on the manifestations of transport-metabolic interactions in intraocular nerve tissue grafts].

Electron microscopic study of intraocular grafts of the septal and hippocampal nervous tissue revealed intensive transport and metabolic interactions between various types of the cells. High level of transport exists between the recipient's blood and intraocular fluid, on the one hand, and the graft, on the other one; the abundance of pinocytotic vesicles in the endothelium, pericytes and the glial end-feet of the capillaries, and the presence of microvilli and cilia on the graft limiting glia. Signs of active communications between interstitial glial cells, as well as between gliocytes and neurons, such as pinocytosis and gap junctions were observed. Similar interactions exist between various parts of nerve cells. Besides, there is an evidence of microphagocytic interactions, particularly between pre- and postsynaptic elements, as shown by the presence of so-called spinules. An unusual fact was observed of internalization of cytoplasmic fragments of the degenerating neuron by contacting synaptic boutons. It is suggested that the high level of transport and metabolic processes may reflect adaptive and compensatory processes in the nervous tissue developing under strict limitations of the neural and neurotrophic influences.

Animals↗

PubMed2000

A kinetic model for the metabolic interaction of two substrates at the active site of cytochrome P450 3A4.

In many cases, CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrates that coexist at the active site. In the present study, we observed that alpha-naphthoflavone (alpha-NF) exhibited a differential effect on CYP3A4-mediated product formation as shown by an increase and decrease, respectively, of the carboxylic acid (P(2)) and omega-3-hydroxylated (P(1)) metabolites of losartan, while losartan was found to be an inhibitor of the formation of the 5,6-epoxide of alpha-NF. Thus, to address this problem, a kinetic model was developed on the assumption that CYP3A4 can accommodate two distinct and independent binding domains for the substrates within the active site, and the resulting velocity equations were employed to predict the kinetic parameters for all possible enzyme-substrate species. Our results indicate that the predicted values had a good fit with the experimental observations. Therefore, the kinetic constants can be used to adequately describe the nature of the metabolic interaction between the two substrates. Applications of the model provide some new insights into the mechanism of drug-drug interactions at the level of CYP3A4.

Benzoflavones↗