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The metabolism of drugs in isolated rat hepatocytes. A comparison with in vivo drug metabolism and drug metabolism in subcellular liver fractions.

The metabolism of drugs in isolated rat hepatocytes has been investigated. Drugs which are metabolized by aromatic hydrolation, aliphatic hydroylation, N-demethylation, or glucuronidation have been used as substrates. With some substrates the rate of metabolism in isolated hepatocytes compares with that in hepatic 900g supernatant fraction or microsomes, but other substrates are metabolized at a slower rate in isolated hepatocytes. For example, the rate of butamoxane hydroxylation in isolated hepatocytes is slower than that in microsomes. However, the rate of hydroxylation is hepatocytes is identical to that in perfused liver. The metabolism of drugs in isolated hepatocytes correlates with in vivo drug metabolism better than does metabolism in the hepatic 9000g supernatant fraction or microsomes.

Animals↗
PubMed2025

Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.

BACKGROUND: The tumor microenvironment (TME) of glioma harbors diverse cell types; however, cell metabolic heterogeneity remains to be explored. This study aims to characterize the metabolic features of different cell types in the TME by integrating multiple datasets, including genomics, bulk and single-cell transcriptomics, and metabolomics. METHODS: Unsupervised machine learning was used to construct an energy metabolic classifier based on the metabolic pathways identified from bulk RNA-seq of gliomas in the TCGA dataset. The classifier was externally validated using multiple datasets, including genomics, bulk RNA-seq, snRNA-seq, and the metabolomics data. Furthermore, metabolic heterogeneity associated with the classifier was further characterized at single-cell resolution. RESULTS: The energy metabolism-based classifier stratified patients into two prognostic clusters: patients in cluster 1 were characterized by high pathway activity of glycolysis, the pentose phosphate pathway (PPP), and fatty acid oxidation (FAO), whereas patients in cluster 2 exhibited higher activity in glutaminolysis. This metabolic classifier revealed both intratumoral and intertumoral metabolic heterogeneity, and the complexity was further validated by the metabolomics profiling and snRNA-seq data from the CPTAC dataset. Notably, OSMR, highly expressed in cluster 1, showed significant co-expression with key glycolytic enzyme genes. The OSM/OSMR/JAK1/STAT3 axis potently drives malignant progression of glioma cells, specially enhancing their invasive and migratory capabilities. Single-cell resolution analyses demonstrated that tumor metabolic heterogeneity is primarily driven by malignant cells rather than non-malignant components, while tumor microenvironment (TME) factors were also found to modulate malignant cell metabolism. Significantly, glycolytic activity in glioma cells increased during the phenotypic transition from PN (proneural) to MES (mesenchymal), with cluster 1 metabolic phenotypes predominating in the tumor core. Compared to cluster 2, cluster 1 patients exhibited higher mRNA expression of immunosuppressive checkpoint genes, which correlated with pronounced immunosuppression in the TME. Furthermore, various immune cells demonstrated distinct metabolic preferences at single-cell resolution. CONCLUSIONS: This study developed an energy metabolic-based classifier for gliomas with prognostic and therapeutic potential. Metabolic reprogramming was linked with the PN-to-MES transition of glioma cells and immunosuppression in the tumor microenvironment. Multi-omics data, especially snRNA-seq, offered insights into metabolism heterogeneity at single-cell resolution, enabling personalized treatment strategies.

Humans↗
PubMed2025

Understanding disease-associated metabolic changes in human colonic epithelial cells using the iColonEpithelium metabolic reconstruction.

The colonic epithelium plays a key role in the host-microbiome interactions, allowing uptake of various nutrients and driving important metabolic processes. To unravel detailed metabolic activities in the human colonic epithelium, our present study focuses on the generation of the first cell-type-specific genome-scale metabolic model (GEM) of human colonic epithelial cells, named iColonEpithelium. GEMs are powerful tools for exploring reactions and metabolites at the systems level and predicting the flux distributions at steady state. Our cell-type-specific iColonEpithelium metabolic reconstruction captures genes specifically expressed in the human colonic epithelial cells. iColonEpithelium is also capable of performing metabolic tasks specific to the colonic epithelium. A unique transport reaction compartment has been included to allow for the simulation of metabolic interactions with the gut microbiome. We used iColonEpithelium to identify metabolic signatures associated with inflammatory bowel disease. We used single-cell RNA sequencing data from Crohn's Diseases (CD) and ulcerative colitis (UC) samples to build disease-specific iColonEpithelium metabolic networks in order to predict metabolic signatures of colonocytes in both healthy and disease states. We identified reactions in nucleotide interconversion, fatty acid synthesis and tryptophan metabolism were differentially regulated in CD and UC conditions, relative to healthy control, which were in accordance with experimental results. The iColonEpithelium metabolic network can be used to identify mechanisms at the cellular level, and we show an initial proof-of-concept for how our tool can be leveraged to explore the metabolic interactions between host and gut microbiota.

Humans↗
PubMed2026

Metabolic Dysfunction-Associated Carcinogenesis: Molecular Mechanisms and the Preventive Roles of Phytochemicals Part I: Pathophysiological Mechanisms Linking Metabolic Dysfunction to Cancer.

The global cancer burden is projected to escalate to 27 million new cases annually by 2040, a trajectory that parallels the rising prevalence of obesity, metabolic dysfunction, and related metabolic disorders. While genetic and environmental factors are well-recognized, the systemic metabolic environment is increasingly identified as a critical determinant of tumorigenesis. This review (Part I) systematically delineates the molecular and cellular framework through which metabolic dysfunction orchestrates a tumor-permissive landscape. We evaluate six primary pathophysiological axes: (1) chronic low-grade inflammation that fuels a protumorigenic milieu, (2) oxidative stress and redox imbalance leading to genomic instability, (3) insulin resistance and insulin-like growth factor axis activation which stimulate mitogenic pathways, (4) aberrant lipid metabolism and lipotoxicity-driven cell transformation, (5) gut microbiota dysbiosis and its modulation of the tumor microenvironment, and (6) metabolism-associated epigenetic remodeling that sustains oncogenic gene expression. Unlike previous literature that has focused on isolated pathways, this synthesis emphasizes the synergistic crosstalk among these mechanisms, illustrating how they collectively reinforce cancer initiation and progression. Furthermore, this mechanistic framework provides a biological rationale for targeting metabolism-associated carcinogenesis through dietary phytochemicals and bioactive compounds, which will be comprehensively discussed in Part II. By providing an integrated overview of the metabolic dysfunction-cancer axis, this work establishes a mechanistic foundation for the preventive potential of phytochemicals. These insights are crucial for developing multitarget dietary strategies against metabolism-associated malignancies.

carcinogenesis↗
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↗
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↗
PubMed1975

[The lipid metabolism of the small intestine and its correlation to the lipid and lipoprotein metabolism of the total organism].

It is attempted to discuss the intestinal lipid metabolism particularly as it relates to systemic lipid and lipoprotein metabolism. In an introductory review of recent concepts of intestinal fat absorption special reference is given to the significance of the mixed lipid micelle during the intraluminal phase of fat absorption, to special morphological and functional features of the lumen-absorptive cell interface and to the proposed role of a fatty acid binding protein in the intracellular transport of long chain fatty acids. Furthermore the metabolic fate of absorbed fatty acids within the absorptive epithelial cell is reviewed and pointed out, that certain proteins (f.i. apoprotein B) are of crucial significance for the export of intestinal lipids into lymph. Absorption of dietary fat, however, is not the only function of the intestine in lipid metabolism. Intestinal mucosa is also capable of de novo synthesis of lipids, a function which is elaborated upon in the discussion of intestinal biosynthesis of cholesterol. Since in addition biosynthesis of cholesterol in the liver has been shown to be under sensitive control of cholesterol in intestinal lymph lipoproteins and the intestine represents the only organ, in which serum cholesterol can be excreted (after conversion to bile salts in the liver), the intestine occupies the central role in cholesterol metabolism. The intensive interrelation of intestinal functions and systemic lipoprotein metabolism is underscored by the more recent finding, that the intestine also synthesizes endogenous lipoproteins, which are secreted constantly into intestinal lymph even in the fasting state, thus contributing to plasma very low density lipoproteins. The intestine is the only organ, in which extrahepatic production of endogenous lipoproteins has been demonstrated. In the special section of this paper own original work is presented, elaborating on intestinal metabolism of plasma free fatty acids (FFA) and dealing with the important question, whether plasma FFA are incorporated into intestinal lymph lipoproteins. Studies were conducted in rats initially, which were given a rapid i.v. injection of labelled fatty acids. Mucosal radioactivity of the small intestine was greatest 2 minutes after i.v. 14C-palmitate, and accounted for 1% of administered isotope. Of mucosal 14C, 42% were present in water soluble metabolites, including CO2 and ketoacids, 28% in phospholipids and only 16% in triglycerides. The specific activity of mucosal triglyceride fatty acids (TGFA) was 11 times that of serum TGFA, confirming triglyceride synthesis by intestinal mucosa. The unexpectedly low percent incorporation of 14C-palmitate into triglycerides and its preferential conversion to water soluble metabolites, reflecting oxidation, were confirmed in double label experiments (3H-palmitate intraluminally, 14C-palmitate i.v.), which showed marked differences in the metabolism of fatty acids entering mucosa simultaneously from the two sources. While i.v...

Adult↗
PubMed2025

Hierarchical metabolic engineering for rewiring cellular metabolism.

Metabolic engineering is a key enabling technology for rewiring cellular metabolism to enhance production of chemicals, biofuels, and materials from renewable resources. However, how to make cells into efficient factories is still challenging due to its robust metabolic networks. To open this door, metabolic engineering has realized great breakthroughs through three waves of technological research and innovations, especially the third wave. To understand the third wave of metabolic engineering better, we discuss its mainstream strategies and examples of its application at five hierarchies, including part, pathway, network, genome, and cell level, and provide insights as to how to rewire cellular metabolism in the context of maximizing product titer, yield, and productivity. Finally, we highlight future perspectives on metabolic engineering for the successful development of cell factories.

Metabolic Engineering↗
PubMed1976

Adenine nucleotide metabolism of blood platelets. IX. Time course of secretion and changes in energy metabolism in thrombin-treated platelets.

Changes in the energy metabolism of washed human platelets were compared with the kinetics of secretion induced by thrombin (5 units/ml). A 50% decrease in the level of metabolic ATP (3H-labelled), which was essentially complete in 30s, was matched in rate by adenine nucleotide secretion from storage in dense granules. Incubation of platelets with antimycin before thrombin addition increased the rate of fall in metabolic ATP, but did not affect the rate of adenine nucleotide secretion. beta-N-Acetylglucosaminidase secretion, which was slower than adenine nucleotide secretion in control platelets, was noticeably inhibited by antimycin, confirming previous reports that different regulatory mechanisms exist for dense and alpha-granule secretion. The rates of rephosphorylation of metabolic ADP to ATP via glycolysis and oxidative phosphorylation were estimated by measuring lactate production and O2 consumption in resting and thrombin-stimulated platelets and compared to the level of metabolic ATP (9-10 nmol/mg of platelet protein in the resting state). The rate of ATP production was stimulated at least two fold from 12 nmol to 24 nmol/min/mg within seconds of thrombin addition. This increased rate was maintained over the observed period of 5 min although the level of metabolic ATP had decreased to 4-5 nmol/mg within 30 s; the turnover of the remaining metabolic ATP thus increased four fold over the resting state although the actual stimulation of energy production was only two fold.

Adenosine Diphosphate↗
PubMed2025

A metabolic atlas of the Klebsiella pneumoniae species complex reveals lineage-specific metabolism and capacity for intra-species co-operation.

The Klebsiella pneumoniae species complex inhabits a wide variety of hosts and environments, and is a major cause of antimicrobial resistant infections. Genomics has revealed the population comprises multiple species/sub-species and hundreds of distinct co-circulating sub-lineage (SLs) that are associated with distinct gene complements. A substantial fraction of the pan-genome is predicted to be involved in metabolic functions and hence these data are consistent with metabolic differentiation at the SL level. However, this has so far remained unsubstantiated because in the past it was not possible to explore metabolic variation at scale. Here, we used a combination of comparative genomics and high-throughput genome-scale metabolic modeling to systematically explore metabolic diversity across the K. pneumoniae species complex (n = 7,835 genomes). We simulated growth outcomes for each isolate using carbon, nitrogen, phosphorus, and sulfur sources under aerobic and anaerobic conditions (n = 1,278 conditions per isolate). We showed that the distributions of metabolic genes and growth capabilities are structured in the population, and confirmed that SLs exhibit unique metabolic profiles. In vitro co-culture experiments demonstrated reciprocal commensalistic cross-feeding between SLs, effectively extending the range of conditions supporting individual growth. We propose that these substrate specializations may promote the existence and persistence of co-circulating SLs by reducing nutrient competition and facilitating commensal interactions. Our findings have implications for understanding the eco-evolutionary dynamics of K. pneumoniae and for the design of novel strategies to prevent opportunistic infections caused by this World Health Organization priority antimicrobial resistant pathogen.

Klebsiella pneumoniae↗
PubMed1978

Drug metabolism in liver disease. Identification of patients with impaired hepatic drug metabolism.

Antipyrine half-life (AP t1/2) was measured in 62 patients with, and 10 control patients without, liver disease to ascertain possible factors which may be useful in identifying patients with abnormal drug metabolism. Antipyrine metabolism was normal or marginally impaired in patients with compensated cirrhosis or acute hepatitis, whereas it was frequently abnormal in those with chronic active hepatitis or advanced alcoholic liver disease. A high degree of correlation was found among AP t1/2 and prothrombin time, hepatic encephalopathy, and ascites. Of patients with severely impaired drug metabolism, 80% had one or more of these features. The severity of histological changes in liver biopsies was of additional help in predicting impaired drug metabolism. Concurrent drug ingestion enhanced antipyrine metabolism in most patients with liver disease as well as in control patients. Inadequate diet was associated with prolongation of AP t1/2, but other environmental factors such as alcohol ingestion, cigarette smoking, and coffee consumption did not affect rates of drug metabolism in patients with liver disease. Consideration of all of the above factors allows qualitative predictions of the rate of hepatic drug metabolism in patients with liver disease, as assessed by the AP t1/2.

Acute Disease↗
PubMed1975

Effects of various cerebral metabolic activators on glucose metabolism of brain.

The effects of various metabolic activators on the glucose metabolism of the perfused cat brain have been investigated. (1) When the perfusion is done with the blood containing cytidine monophosphate, the glucose metabolism of the brain is enhanced, as compared to the perfusion with the blood without cytidine monophosphate. There is no marked change in the cerebral metabolic rate and in the contents of intermediate metabolite of glucose in the brain. (2) Citicoline enhances the incorporation of blood glucose into the brain and its metabolism in the brain. It increases slightly the cerebral blood flow rate and decreases the accumulation of lactate in the brain. (3) Either Pyrithioxin or Meclophenoxate has no effect on the glucose metabolism of the brain nor on the cerebral metabolic rate.

Animals↗
PubMed1977

[Behavior of certain parameters of lipid and energy metabolism. IV. Regulation of lipid and energy metabolism in livers and race and mini pigs].

To characterize the lipid and the energy metabolism in the livers of genetically different types of pigs (land race pig and mini pig), the authors determined the activities of enzymes typical of and limiting these metabolic pathways. Furthermore, they measured the concentrations of typical metabolites and ascertained parameters that are of importance in energy metabolism. The concentrations of acetyl CoA and free fatty acids in the livers of mini pigs were significantly greater than those in the livers of land race pigs, whereas the cholesterol, glycerol, triglyceride and acetoacetate concentrations were reduced. The activities of glucose-6-phosphate dehydrogenase (E.C.1.1.1.49.), citrate synthase (E.C.4.1.3.7.) and ATP citrate lyase (E.C.4.1.3.8.) were lower in the livers of mini pigs than in the livers of land race pigs, whereas the activity of fatty acid synthase was higher. The concentrations of cyclic 3',5'-adenosine monophosphate (AMP) and adenosine diphosphate (ADP) were lower in the livers of mini pigs than in those of land race pigs. In land race pigs, the metabolic process seems, therefore, to be determined in favour of the degradation of free fatty acids and of the generation of energy. In mini pigs, lipogenesis in the liver appears to be the decisive metabolic pathway. The possibility of a higher coordinating control mechanism of the lipid and the energy metabolism is discussed.

ATP Citrate (pro-S)-Lyase↗
PubMed2025

C6ORF120 regulates hepatic lipid metabolism through PPAR signaling pathway in metabolic dysfunction-associated steatotic liver disease.

Background Emerging evidence indicates that C6ORF120 is highly expressed in the liver and may modulate immune responses in various hepatic disorders. However, its role in hepatic lipid metabolism and metabolic dysfunction-associated steatotic liver disease (MASLD) is unexplored. This study aimed to elucidate the effects and potential mechanisms of C6ORF120 on hepatic lipogenesis. Methods C6ORF120 expression in MASLD was assessed using patient serum and the Gene Expression Omnibus (GEO) database. A high-fat diet-induced MASLD model was established in C6orf120-KO rats. Fatty acid-induced lipid accumulation models were generated in primary hepatocytes, HepG2 and Huh7 cells. These models were employed to investigate the effects of C6ORF120 on hepatic lipogenesis and MASLD progression. Results C6ORF120 expression was significantly upregulated in MASLD patients and obese rat models. Genetic deletion of C6ORF120 markedly alleviated high-fat diet-induced steatosis in the liver of rats. In vitro, C6orf120 gene deficiency attenuated lipid accumulation and suppressed key lipogenic genes (such as fatty acid synthase (Fasn), phospho-acetyl coenzyme carboxylase (p-ACC), sterol regulatory element binding protein-1c (Srebp1c)) in primary hepatocytes and HepG2 cells. Conversely, C6ORF120 overexpression increased lipid accumulation in HepG2 cells. RNA sequencing analysis showed that lipid metabolism pathway and peroxisome proliferators activated receptor (PPAR) signaling pathway were significantly altered in the liver of C6orf120-KO rats. We demonstrated that C6ORF120 may regulate lipid metabolism through the hepatic PPARα, which is involved in fatty acid production and lipid oxidation. Further, we found that serum C6ORF120 expression was correlated with clinical indicators in patients with MASLD. Conclusion This study preliminarily revealed a novel function for C6ORF120 in hepatic lipid metabolism via affecting the PPAR pathway. The result identifies C6ORF120 as a novel regulator of hepatic lipid metabolism through PPARα-dependent mechanisms, offering potential therapeutic targets for MASLD.

Lipid Metabolism↗
PubMed1979

Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes.

The concentration of cytochrome P-450 and activities of the microsomal enzymes aryl hydrocarbon hydroxylase and ethylmorphine demethylase were measured in hepatic tissue obtained at biopsy from 69 patients. Antipyrine half-life (AP t1/2) was measured simultaneously as an in vivo marker of drug metabolism. Values for each index of the drug-metabolizing system varied greatly, but the mean values in groups of patients with mild hepatitis or inactive cirrhosis did not differ significantly from those of controls. Hepatic cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were lower in patients with severe hepatitis or active cirrhosis than in controls, but ethylmorphine demethylase activity was unchanged in the patients. Drug ingestion was associated with enhancement of drug-metabolizing enzymes in all patients but those with severe liver disease; ethylmorphine demethylase activity was enhanced proportionately more than aryl hydrocarbon hydroxylase activity or cytochrome P-450 concentration. The observation that aryl hydrocarbon hydroxylase and ethylmorphine demethylase activities are influenced to a different extent by liver disease and also by drug ingestion indicates functional heterogeneity of the hepatic microsomal drug-metabolizing system in man. Correlations between t1/2 and hepatic drug oxidases were weak, even when allowance was made for variation in liver size. Thus, the rate of drug metabolism in vivo assessed by measuring AP t1/2 does not appear to be closely related to the activity of some hepatic drug-metabolizing enzymes.

Antipyrine↗