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PubMed2000

1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3: analogs of 1alpha,25-dihydroxyvitamin D3 that resist metabolism through the C-24 oxidation pathway are metabolized through the C-3 epimerization pathway.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the previously well established main side chain modification pathway, is initiated by hydroxylation at C-24 of the side chain. The C-3 epimerization pathway, the newly discovered A-ring modification pathway, is initiated by epimerization of the hydroxyl group at C-3 of the A-ring. The end products of the metabolism of 1alpha,25(OH)2D3 through the C-24 oxidation and the C-3 epimerization pathways are calcitroic acid and 1alpha,25-dihydroxy-3-epi-vitamin-D3 respectively. During the past two decades, numerous noncalcemic analogs of 1alpha,25(OH)2D3 were synthesized. Several of the analogs have altered side chain structures and as a result some of these analogs have been shown to resist their metabolism through side chain modifications. For example, two of the analogs, namely, 1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 [1alpha,25(OH)2-16-ene-23-yne-D3] and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3 [1alpha,25(OH)2-16-ene-23-yne-20-epi-D3], have been shown to resist their metabolism through the C-24 oxidation pathway. However, the possibility of the metabolism of these two analogs through the C-3 epimerization pathway has not been studied. Therefore, in our present study, we investigated the metabolism of these two analogs in rat osteosarcoma cells (UMR 106) which are known to express the C-3 epimerization pathway. The results of our study indicate that both analogs [1alpha,25(OH)2-16-ene-23-yne-D3 and 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3] are metabolized through the C-3 epimerization pathway in UMR 106 cells. The identity of the C-3 epimer of 1alpha,25(OH)2-16-ene-23-yne-D3 [1alpha,25(OH)2-16-ene-23-yne-3-epi-D3] was confirmed by GC/MS analysis and its comigration with synthetic 1alpha,25(OH)2-16-ene-23-yne-3-epi-D3 on both straight and reverse-phase HPLC systems. The identity of the C-3 epimer of 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3 [1alpha,25(OH)2-16-ene-23-yne-20-epi-3-epi-D3] was confirmed by GC/MS and 1H NMR analysis. Thus, we indicate that vitamin D analogs which resist their metabolism through the C-24 oxidation pathway, have the potential to be metabolized through the C-3 epimerization pathway. In our present study, we also noted that the rate of C-3 epimerization of 1alpha,25(OH)2-16-ene-23-yne-20-epi-D3 is about 10 times greater than the rate of C-3 epimerization of 1alpha,25(OH)2-16-ene-23-yne-D3. Thus, we indicate for the first time that certain structural modifications of the side chain such as 20-epi modification can alter significantly the rate of C-3 epimerization of vitamin D compounds.

Animals↗
PubMed1983

[Relation between serum lipoprotein metabolism and biliary lipid metabolism].

This review concern with recent results regarding interrelationships between serum lipoprotein and bile acid metabolism. First, changes in bile acid metabolism in primary hyperlipoproteinaemia type II and type IV are described. In addition, influences of lipid-lowering drugs such as sitosterol, cholestyramine/colestipol, neomycin, nicotinic acid, clofibrate and thyroxin on serum lipoproteins and biliary lipid metabolism are discussed. Changes in lipoprotein metabolism in disorders of bile acid metabolism and effects of primary and secundary bile acids on lipoprotein metabolism, hepatic cholesterol metabolism and intestinal cholesterol absorption are described. In the final discussion interrelationships between very low density lipoprotein - triglycerides and cholic acid metabolism as well as low density lipoprotein and chenodeoxycholic acid metabolism are stressed. The positive correlation between serum triglycerides and lithogenicity of bile is underlined and the possible significance of high density lipoprotein-cholesterol as precursor of biliary cholesterol is discussed.

Bile↗
PubMed1986

Progesterone metabolism in T47Dco human breast cancer cells--II. Intracellular metabolic path of progesterone and synthetic progestins.

We show here that progesterone added to the medium of proliferating T47Dco human breast cancer cells is metabolized with a half life of 2-4h. The final metabolic product, 5 alpha-pregnan-3 beta,6 alpha-diol-20-one, (P-metabolite) is released into the medium. This structure suggested that the intracellular metabolism of progesterone involves the enzymes 5 alpha-reductase, 3 beta-hydroxysteroid dehydrogenase, and 6 alpha-hydroxylase. To investigate this pathway, the cells were incubated with a variety of potential substrates. In addition to progesterone, only precursors with the 5 alpha-configuration served as substrates for the enzymes leading to P-metabolite formation. Some precursors with a 5 beta-configuration were also metabolized by T47Dco cells. This metabolism reflected activity by either 3 beta-hydroxysteroid dehydrogenase and/or 6 alpha-hydroxylase but, in contrast to progesterone metabolism, the rates were different and the products were often mixtures. In T47Dco and MCF-7 human breast tumor cells, the reduction at C-3 followed by 6 alpha-hydroxylation, appear to be the major, and possibly only, route of progesterone metabolism. In contrast, preliminary data suggest that in normal human breast epithelial cells, this is not an exclusive route. Androgens are partially subject to the same metabolic enzymes, but synthetic progestins are not metabolized by T47Dco during an 18 h incubation.

3-Hydroxysteroid Dehydrogenases↗
PubMed1978

Glutamine metabolism in the kidney during induction of, and recovery from, metabolic acidosis in the rat.

Experiments were carried out on rats to evaluate the possible regulatory roles of renal glutaminase activity, mitochondrial permeability to glutamine, phosphoenolpyruvate carboxykinase activity and systemic acid-base changes in the control of renal ammonia (NH(3) plus NH(4) (+)) production. Acidosis was induced by drinking NH(4)Cl solution ad libitum. A pronounced metabolic acidosis without respiratory compensation [pH=7.25; HCO(3) (-)=16.9mequiv./litre; pCO(2)=40.7mmHg (5.41kPa)] was evident for the first 2 days, but thereafter acid-base status returned towards normal. This improvement in acid-base status was accompanied by the attainment of maximal rates of ammonia excretion (onset phase) after about 2 days. A steady rate of ammonia excretion was then maintained (plateau phase) until the rats were supplied with tap water in place of the NH(4)Cl solution, whereupon pCO(2) and HCO(3) (-) became elevated [55.4mmHg (7.37kPa) and 35.5mequiv./litre] and renal ammonia excretion returned to control values within 1 day (recovery phase). Renal arteriovenous differences for glutamine always paralleled rates of ammonia excretion. Phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase activities and the rate of glutamine metabolism (NH(3) production and O(2) consumption) by isolated kidney mitochondria all increased during the onset phase. The increases in glutaminase and in mitochondrial metabolism continued into the plateau phase, whereas the increase in the carboxykinase reached a plateau at the same time as did ammonia excretion. During the recovery phase a rapid decrease in carboxykinase activity accompanied the decrease in ammonia excretion, whereas glutaminase and mitochondrial glutamine metabolism in vitro remained elevated. The metabolism of glutamine by kidney-cortex slices (ammonia, glutamate and glucose production) paralleled the metabolism of glutamine in vivo during recovery, i.e. it returned to control values. The results indicate that the adaptations in mitochondrial glutamine metabolism must be regulated by extra-mitochondrial factors, since glutamine metabolism in vivo and in slices returns to control values during recovery, whereas the mitochondrial metabolism of glutamine remains elevated.

Acid-Base Equilibrium↗
PubMed2002

In vitro identification of metabolic pathways and cytochrome P450 enzymes involved in the metabolism of etoperidone.

1. In vitro studies have been carried out to investigate the metabolic pathways and identify the hepatic cytochrome P450 (CYP) enzymes involved in etoperidone (Et) metabolism. 2. Ten in vitro metabolites were profiled, quantified and tentatively identified after incubation with human hepatic S9 fractions. Et was metabolized via three metabolic pathways: (A) alkyl hydroxylation to form OH-ethyl-Et (M1); (B) phenyl hydroxylation to form OH-phenyl-Et (M2); and (C) N-dealkylation to form 1-m-chlorophenylpiperazine (mCPP, M8) and triazole propyl aldehyde (M6). Six additional metabolites were formed by further metabolism of M1, M2, M6 and M8. 3. Kinetic studies revealed that all metabolic pathways were monophasic, and the pathway leading to the formation of OH-ethyl-Et was the most efficient at eliminating the drug. On incubation with microsomes expressing individual recombinant CYPs, formation rates of M1-3 and M8 were 10-100-fold greater for CYP3A4 than that for other CYP forms. The formation of these metabolites was markedly inhibited by the CYP3A4-specific inhibitor ketoconazole, whereas other CYP-specific inhibitors did not show significant effects. In addition, the production of M1-3 and M8 was strongly correlated with CYP3A4-mediated testosterone 6beta-hydroxylase activities in 13 different human liver microsome samples. 4. Dealkylation of the major metabolite M1 to form mCPP (M8) was also investigated using microsomes containing recombinant CYP enzymes. The rate of conversion of M1 to mCPP by CYP3A4 was 503.0 +/- 3.1 pmole nmole(-1) min(-1). Metabolism of M1 to M8 by other CYP enzymes was insignificant. In addition, this metabolism in human liver microsomes was extensively inhibited by the CYP3A4 inhibitor ketoconazole, but not by other CYP-specific inhibitors. In addition, conversion of M1 to M8 was highly correlated with CYP3A4-mediated testosterone 6beta-hydroxylase activity. 5. The results strongly suggest that CYP3A4 is the predominant enzyme-metabolizing Et in humans.

Chromatography, Liquid↗
PubMedDate not supplied

New hepatocyte in vitro systems for drug metabolism: metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures.

Primary hepatocytes represent a well-accepted in vitro cell culture system for studies of drug metabolism, enzyme induction, transplantation, viral hepatitis, and hepatocyte regeneration. Recently, a multicentric research program has been initiated to optimize and standardize new in vitro systems with hepatocytes. In this article, we discuss five of these in vitro systems: hepatocytes in suspension, perifusion culture systems, liver slices, co-culture systems of hepatocytes with intestinal bacteria, and 96-well plate bioreactors. From a technical point of view, freshly isolated or cryopreserved hepatocytes in suspension represent a readily available and easy-to-handle in vitro system that can be used to characterize the metabolism of test substances. Hepatocytes in suspension correctly predict interspecies differences in drug metabolism, which is demonstrated with pantoprazole and propafenone. A limitation of the hepatocyte suspensions is the length of the incubation period, which should not exceed 4hr. This incubation period is sufficiently long to determine the metabolic stability and to allow identification of the main metabolites of a test substance, but may be too short to allow generation of some minor, particularly phase II metabolites, that contribute less than 3% to total metabolism. To achieve longer incubation periods, hepatocyte culture systems or bioreactors are used. In this research program, two bioreactor systems have been optimized: the perifusion culture system and 96-well plate bioreactors. The perifusion culture system consists of collagen-coated slides allowing the continuous superfusion of a hepatocyte monolayer with culture medium as well as establishment of a constant atmosphere of 13% oxygen, 82% nitrogen, and 5% CO2. This system is stable for at least 2 weeks and guarantees a remarkable sensitivity to enzyme induction, even if weak inducers are tested. A particular advantage of this systemis that the same bioreactor can be perfused with different concentrations of a test substance in a sequential manner. The 96-well plate bioreactor runs 96 modules in parallel for pharmacokinetic testing under aerobic culture conditions. This system combines the advantages of a three-dimensional culture system in collagen gel, controlled oxygen supply, and constant culture medium conditions, with the possibility of high throughput and automatization. A newly developed co-culture system of hepatocytes with intestinal bacteria offers the possibility to study the metabolic interaction between liver and intestinal microflora. It consists of two chambers separated by a permeable polycarbonate membrane, where hepatocytes are cultured under aerobic and intestinal bacteria in anaerobic conditions. Test substances are added to the aerobic side to allow their initial metabolism by the hepatocytes, followed by the metabolism by intestinal bacteria at the anaerobic side. Precision-cut slices represent an alternative to isolated hepatocytes and have been used fo the investigation of hepatic metabolism, hepatotoxicity, and enzyme induction. A specific advantage of liver slices is the possibility to study toxic effects on hepatocytes that are mediated or modified by nonparenchymal cells (e.g., by cytokine release from Kupffer cells) because the physiological liver microarchitecture is maintained in cultured slices. For all these in vitro systems, a prevalidation has been performed using standard assays for phase I and II enzymes. Representative results with test substances and recommendations for application of these in vitro systems, as well as standard operation procedures are given.

Animals↗
PubMed1972

Pathways of glutamine and organic acid metabolism in renal cortex in chronic metabolic acidosis.

The metabolism of labeled glutamine and of several labeled organic acid anions was compared in tissue slices of renal cortex from chronically acidotic and alkalotic littermate dogs. (15)NH(3) formation and (15)N-amideglutamine utilization were significantly increased by slices from acidotic animals providing further evidence for the similarity of the metabolic responses seen in the tissue slice system and the physiologic effects produced by chronic metabolic acidosis on renal metabolism in the intact animal. Slices from acidotic dogs formed more (14)CO(2) and glucose-(14)C than did slices from alkalotic animals when labeled glutamine, citrate, or malate was used as substrate but (14)CO(2) production from pyruvate-1-(14)C was slightly reduced in acidotic tissue. With most of the substrates used glucose-(14)C formation was small compared with (14)CO(2) formation. Using the amount of glucose-(14)C formed, the expected (14)CO(2) production was calculated based on the hypothesis that the primary site of action of metabolic acidosis is on a cytoplasmic step in gluconeogenesis. The actual difference in (14)CO(2) production between slices from acidotic and alkalotic animals always greatly exceeded this predicted amount, indicating that stimulation of gluconeogenesis represents a minor metabolic response to chronic metabolic acidosis. Evidence from experiments with citrate labeled in various positions showed that metabolic acidosis has its principal effect on an early step in substrate metabolism which must be intramitochondrial in location.

Acidosis↗
PubMed1992

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed1992

Kinin metabolism in the perfused ventilated rat lung. II: Influence of ventilation, perfusion, and perfusate composition variation on bradykinin metabolism in uninjured lung.

Bradykinin metabolism by peptidases of the pulmonary endothelium has been investigated in the previously uninjured, ventilated, and asanguinously perfused rat lung. The influence of short-duration (up to 20 min) abnormal ventilation and perfusion conditions on bradykinin metabolism was assessed. Neither variation of the oxygen concentration (0 to 45%) nor omission of carbon dioxide in the ventilatory gas altered bradykinin metabolism significantly. Tidal volume variation did not alter bradykinin metabolism, and exclusion of one lung from the perfusion circuit reduced the capacity to degrade bradykinin proportionately. Acidification of the perfusion medium to pH 5 did not alter bradykinin metabolism. Acetylsalicylic acid in the perfusate protected the lung from an otherwise irreversible pressure increase associated with high-dose bradykinin perfusion. Endotoxin and hydrogen peroxide in the perfusate did not alter bradykinin metabolism. However, ammonia in the ventilatory gas caused immediate pulmonary edema, diminished lung capacity to metabolize bradykinin and altered the pattern of bradykinin metabolic products. The pulmonary endothelium itself, in the absence of blood, maintains its capacity to metabolize bradykinin under an extraordinary range of conditions.

Amino Acid Sequence↗
PubMed1992

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 7th communication: in vitro metabolism.

In order to clarify the sites of metabolism and the metabolizing enzymes of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1- ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), metabolism studies were carried out using rat, dog, monkey, and human plasma and rat tissue homogenates. After incubating with the various plasma samples, imidapril was mainly metabolized to the pharmacologically active metabolite, 6366 A (M1, CAS 89371-44-8), in rat plasma; on the other hand, the ester bond of imidapril was not hydrolyzed in dog, monkey, and human plasma. Imidapril was metabolized to M1, M2, M3, and M4 in all rat tissue homogenates tested. Aside from the above metabolites, no other metabolites were detected. The metabolic activity of imidapril to M1 was the highest in the liver, followed by the kidney and lung; however, it was low in other tissue homogenates. From the results of experiments using certain esterase inhibitors, it has been concluded that the metabolic conversion of imidapril to M1 is mainly due to a carboxylesterase (B-esterase). In contrast, the metabolic activity of imidapril to M2 and M3 (or M4) was highest in the kidney and small intestine while low in other tissues. From the experiments using certain enzyme inhibitors, it has been found that an acetylesterase (C-esterase) is largely involved in the metabolism of imidapril into M2 and M3.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Calcitriol metabolism during chronic metabolic acidosis.

Chronic metabolic acidosis causes a profound disturbance in renal proximal tubule 1OHase activity through perturbation of the normal ionic and hormonal controls of the enzyme activity. A lack of enzyme stimulation in response to hypophosphatemia and a paradoxical response of increased 1OHase activity to increased extracellular phosphorus are the important extracellular markers of deranged P control of 1OHase activity during chronic metabolic acidosis. 1OHase activity is down-regulated during chronic metabolic acidosis by an increase in renal cortical tubule mitochondrial calcium content and a functional abnormality in calcium handling, a reduction in extramitochondrial buffering capacity. There is a defect in PTH regulation of 1OHase during chronic metabolic acidosis, despite PTH levels which are inappropriately normal in relation to ionized hypercalcemia. PTH-directed cAMP accumulation is likely normal as well. Metabolic clearance of calcitriol is increased during chronic metabolic acidosis. Thus, the hormonal stimulus to maintain calcium and phosphorus homeostasis, calcitriol, is so altered by chronic metabolic acidosis that it is easy to understand the profound clinical effects of the acidosis on the skeleton of growing children. Chronic metabolic acidosis has allowed a greater understanding of the complex regulatory physiology that underlies renal proximal tubular 1OHase activity and calcitriol metabolism.

Acidosis, Renal Tubular↗
PubMed1988

Regulation of cyclic GMP metabolism in toad photoreceptors. Definition of the metabolic events subserving photoexcited and attenuated states.

Photoreceptor metabolism of cGMP and its regulation were characterized in isolated toad retinas by determining the intensity and time dependence of light-induced changes in the following metabolic parameters: cGMP hydrolytic flux determined by the rate of 18O incorporation from 18O-water into retinal guanine nucleotide alpha-phosphoryls; changes in the total (protein-bound and unbound) concentrations of the guanine nucleotide metabolic intermediates; and changes in the concentration of metabolic (unbound) GDP calculated from the fraction of the alpha-GDP that undergoes labeling with 18O. The latter is interpreted to reflect the state of the equilibrium between GDP- and GTP-complexed forms of G-protein. With narrow band 500 nm light that preferentially stimulates red rod photoreceptors, a range of intensities covering approximately 5 log units produced increases of over 10-fold in cGMP metabolic flux. However, the characteristics of the cGMP metabolic response over the first 2.5 log units of intensity are readily distinguishable from those at higher intensities which exhibit progressive attenuation by an intensity- and time-dependent process. Over the range of low intensities (0.6-3 log photons.micron-2.s-1) the metabolic response is characterized by 1) increases in cGMP hydrolytic flux of up to 8-fold as a logarithmic function of intensity of photic stimulation that are sustained for at least 200 s; 2) small increases or no change in the concentration of total cGMP; 3) large increases of up to 10-fold in the concentration of metabolically active GDP as a linear function of intensity with no significant change in the tissue concentrations of total GDP or GTP; and 4) amplification of the photosignal by the metabolism of approximately 10,000 molecules of cGMP per photoisomerization with the major site of amplification at the level of the interaction of bleached rhodopsin with G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Enhancement of rat liver microsomal metabolism of azoxymethane to methylazoxymethanol by chronic ethanol administration: similarity to the microsomal metabolism of N-nitrosodimethylamine.

We compared the metabolism of azoxymethane (AOM) and of N-nitrosodimethylamine (NDMA) by liver microsomes obtained from male F344 rats pair-fed for 3 weeks either a control liquid diet or an isocaloric liquid diet containing ethanol at a concentration of 6.6% by volume. High-performance liquid chromatographic analysis of the products of the microsomal metabolism of AOM showed that methylazoxymethanol was the only primary metabolite. While the formation of small (less than 4% of methylazoxymethanol) quantities of methanol and formaldehyde could also be detected in this reaction, these products could be accounted for almost entirely by the spontaneous decomposition of methylazoxymethanol. With NDMA as the substrate in the incubation system, the formation of methylamine, formaldehyde, methanol, and an additional, as yet unidentified metabolite was detected. Liver microsomes obtained from rats fed the ethanol-containing diet up to the time of sacrifice were 12-18 times more active in the metabolism of both AOM and NDMA than liver microsomes obtained from rats fed the control, ethanol-free diet for the same period. When rats fed the ethanol diet for 20.5 days were fed the control diet for 0.5 days and then sacrificed, only a 2- to 3-fold increase in the metabolism of both AOM and NDMA by liver microsomes was observed, indicating that cessation of ethanol intake results in a rapid decrease of the ethanol-induced metabolic enzymes. Hepatocytes isolated from ethanol-fed rats showed a significantly enhanced sensitivity to AOM- as well as to NDMA-induced unscheduled DNA synthesis, indicating that the increased rate of microsomal metabolism induced by ethanol is associated with enhanced carcinogen activation in vitro. The metabolism of AOM and NDMA by liver microsomes was inhibited to similar extents by carbon monoxide, pyrazole, sodium azide, aminoacetonitrile, imidazole, and ethanol. In addition, both ethanol and NDMA were found to inhibit competitively the microsomal metabolism of AOM. These results suggest that AOM and NDMA are metabolized by very similar, indeed perhaps the same rat liver microsomal enzyme(s).

Animals↗
PubMed1984

Interactions between folate metabolism, phenytoin metabolism, and liver microsomal cytochrome P450.

The majority of epileptic patients treated with phenytoin (DPH) develop a drug-related decrease in serum folate levels. In the present study the hypothesis was investigated that increased folate utilization for DPH metabolism or for enzyme induction may contribute to the mechanism by which DPH induces folate deficiency. In addition, the effect of folate deficiency on microsomal enzyme induction was determined. Sprague-Dawley rats were fed AIN-76 diet which contained either no folate or 2 mg/kg folic acid. The DPH metabolism as well as the folate-dependent oxidation of formate and histidine and the metabolism of model substrates of microsomal cytochrome P450 (ethoxycourmarin and p-nitroanisole) were measured in hepatocytes isolated from these rats. Hepatocyte concentrations of cytochrome P450 were also determined. Cells from rats fed folate-deficient diet had reduced concentrations of folate, but the cytochrome P450 concentrations were unchanged. Phenobarbital increased cytochrome P450 concentration to an equal extent in both diet groups, but it had no effect on liver folate levels. Phenytoin, at the dose given, did not induce cytochrome P450, but a small increase in the metabolism of DPH, p-nitroanisole, and ethoxycoumarin was observed. The metabolism of formate and histidine to CO2 was decreased in folate-deficient cells but not altered by phenobarbital pretreatment. Ethoxycoumarin and p-nitroanisole metabolism were the same in control and folate-deficient hepatocytes, and the rates were increased in both diet groups by phenobarbital pretreatment. The rate of DPH metabolism was unaltered by folate deficiency and the rate was increased by phenobarbital pretreatment in both folate-deficient and control cells. The results of these experiments show that hepatic DPH metabolism is not dependent upon the cellular concentration of folates. Furthermore, folate deficiency does not alter the activity of the liver microsomal cytochrome P450 system or its inducibility. The results suggest that the folate deficiency induced by DPH is not due to utilization of folates in DPH metabolism.

Animals↗
PubMed2006

Metabolic organization of the spotted ratfish, Hydrolagus colliei (Holocephali: Chimaeriformes): insight into the evolution of energy metabolism in the chondrichthyan fishes.

The metabolic organization of a holocephalan, the spotted ratfish (Hydrolagus colliei), was assessed using measurements of key enzymes of several metabolic pathways in four tissues and plasma concentrations of free amino acids (FAA) and non-esterified fatty acids (NEFA) to ascertain if the Holocephali differ metabolically from the Elasmobranchii since these groups diverged ca. 400 Mya. Activities of carnitine palmitoyl transferase indicate that fatty acid oxidation occurs in liver and kidney but not in heart or white muscle. This result mirrors the well-established absence of lipid oxidation in elasmobranch muscle, and more recent studies showing that elasmobranch kidney possesses a capacity for lipid oxidation. High activities in oxidative tissues of enzymes of ketone body metabolism, including D-beta-hydroxybutyrate dehydrogenase, indicate that, like elasmobranchs, ketone bodies are of central importance in spotted ratfish. Like many carnivorous fishes, enzyme activities demonstrate that amino acids are metabolically important, although the concentration of plasma FAA was relatively low. NEFA concentrations are lower than in teleosts, but higher than in most elasmobranchs and similar to that in some "primitive" ray-finned fishes. NEFA composition is comparable to other marine temperate fishes, including high levels of n-6 and especially n-3 polyunsaturated fatty acids. The metabolic organization of the spotted ratfish is similar to that of elasmobranchs: a reduced capacity for lipid oxidation in muscle, lower plasma NEFA levels, and an emphasis on ketone bodies as oxidative fuel. This metabolic strategy was likely present in the common chondrichthyan ancestor, and may be similar to the ancestral metabolic state of fishes.

Amino Acids↗
PubMed2026

In silico analysis and comparison of the metabolic capabilities of different organisms by reducing metabolic complexity.

BACKGROUND: Understanding how metabolic capabilities diverge across microbial species is essential for deciphering community function, ecological interactions, and the design of synthetic microbiomes. Despite shared core pathways, microbial phenotypes can differ markedly due to evolutionary adaptations and metabolic specialization. Genome-scale metabolic models (GEMs) provide a systems-level framework to explore these differences; however, their complexity hinders direct comparison. RESULTS: We introduce NIS (Neidhardt-Ingraham-Schaechter), a computational workflow that integrates the redGEM, lumpGEM, and redGEMX algorithms to systematically reduce genome-scale models into biologically interpretable modules. This approach enables direct, quantitative comparison of fueling pathways, biomass biosynthetic routes, and environmental exchange processes while retaining essential metabolic information. We first demonstrate the utility of NIS by analyzing Escherichia coli and Saccharomyces cerevisiae, which revealed both conserved and divergent strategies in central metabolism, biosynthetic cost, and substrate utilization. We then applied NIS to the core honeybee gut microbiome, uncovering distinct metabolic traits, functional redundancy, and complementarity that help explain auxotrophy, cross-feeding interactions, and microbial coexistence. CONCLUSIONS: NIS provides an automated, scalable, and reproducible framework for dissecting microbial metabolic networks beyond gene content or taxonomy. By linking metabolism to ecological function, NIS offers new opportunities to interpret microbial community dynamics and to support the rational design of microbiomes in health, agriculture, and environmental applications. Video Abstract.

Metabolic Networks and Pathways↗
PubMed2005

Thermodynamically based profiling of drug metabolism and drug-drug metabolic interactions: a case study of acetaminophen and ethanol toxic interaction.

Drug-drug metabolic interactions can result in unwanted side effects, including reduced drug efficacy and formation of toxic metabolic intermediates. In this work, thermodynamic constraints on non-equilibrium metabolite concentrations are used to reveal the biochemical interactions between the metabolic pathways of ethanol and acetaminophen (N-acetyl-p-aminophenol), two drugs known to interact unfavorably. It is known that many reactions of these pathways are coupled to the central energy metabolic reactions through a number of metabolites and the cellular redox potential. Based on these observations, a metabolic network model has been constructed and a database of thermodynamic properties for all participating metabolites and reactions has been compiled. Constraint-based computational analysis of the feasible metabolite concentrations reveals that the non-toxic pathways for APAP metabolism and the pathway for detoxifying N-acetyl-p-benzoquinoneimine (NAPQI) are inhibited by network interactions with ethanol metabolism. These results point to the potential utility of thermodynamically based profiling of metabolic network interactions in screening of drug candidates and analysis of potential toxicity.

Acetaminophen↗
PubMed2006

Long-term cardiac rehabilitation and exercise training programs improve metabolic parameters in metabolic syndrome patients with and without coronary heart disease.

BACKGROUND AND AIMS: The effectiveness of long-term cardiac rehabilitation and exercise training programs on metabolic parameters was evaluated in metabolic syndrome subjects with and without coronary heart disease (CHD). METHODS AND RESULTS: Fifty-nine CHD and 81 non-coronary patients with metabolic syndrome (59+/-8 vs 56+/-9years) were identified retrospectively at entry into identical cardiac rehabilitation and exercise-training programs. Metabolic syndrome was defined using modified Adult Treatment Panel III criteria. Exercise training occurred approximately twice per week. Metabolic and exercise testing data were collected at baseline and after 12months during the course of the program. Mean duration of cardiac rehabilitation and exercise training programs was over one year in both coronary and non-coronary patients (366+/-111 vs 414+/-102days for CHD and non-coronary CHD cohorts respectively, p<0.01). Significant improvements in bodyweight, body mass index, blood lipids, triglyceride/HDL ratio and exercise tolerance were noted in both cohorts. At the end of follow-up, 31% of CHD and 20% of non-CHD subjects no longer possessed diagnostic criteria for metabolic syndrome (p<0.0001 and p<0.001 respectively). CONCLUSIONS: A long-term cardiac rehabilitation program reduces metabolic syndrome prevalence in CHD patients and results in a similar improvement in risk factor control for metabolic syndrome patients without CHD.

Aged↗