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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↗
PubMed2001

Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism?

Ultrarapid drug metabolism mediated by CYP2D6 is associated with inheritance of alleles with duplicated or amplified functional CYP2D6 genes. However, genotyping for duplicated CYP2D6 alleles only explains a fraction (10-30%) of the ultrarapid metabolizer phenotypes observed in Caucasian populations. Using a sample of CYP2D6 duplication-negative ultrarapid metabolizer subjects and selected control subjects with extensive metabolism, we examined parts of the CYP2D7 pseudogene, and the promoter region and 5'-coding sequence of CYP2D6 for polymorphisms possibly associated with the ultrarapid metabolizer phenotype. In an initial screening of 17 subjects (13 ultrarapid metabolizers and four extensive metabolizers), we identified three DNA variants in the 5'-end of the CYP2D7 pseudogene and 29 variants in the 5'-end of the CYP2D6 gene. Five variants were then selected for examination in a larger sample of subjects having the ultrarapid metabolizer (n = 27) or extensive metabolizer phenotype (n = 77). Subsequent statistical analyses of allele, genotype and estimated haplotype distributions showed that the 31A allele of the 31G > A (Val(II)Met) polymorphism was significantly more frequent in ultrarapid metabolizer subjects than in extensive metabolizer subjects (P = 0.04). Also, estimation of haplotype frequencies suggested that one of the haplotypes with the 31A variant was significantly more frequent among the ultrarapid metabolizers compared with the extensive metabolizers (P = 0.03). The average metabolic ratio was significantly lower in subjects possessing the 31A allele compared with subjects homozygous for the 31G allele (P = 0.02). We also observed a nonsignificant over-representation of the G-allele of a - 1584 C > G promoter polymorphism in the ultrarapid metabolizer group. Since our results are based on a relatively low number of subjects, further studies on larger samples and functional analyses of the polymorphisms detected are necessary to determine the role of the 31G > A and - 1584C > 6 variants in CYP2D6 duplication-negative ultrarapid metabolizer subjects.

5' Untranslated Regions↗
PubMed1985

[Methodological aspects of the determination of nitrogen metabolism parameters from 15N-tracer experiments on swine based on nitrogen metabolism models. 2. Calculation of N metabolism parameters from the time of urinary excretion of 15N].

After a 45-hour infusion of 15N-lysine and 15N-glycine resp. with pigs of 25 kg live weight, the infusion of the tracer was disrupted and a 3-day reduction phase was made part of the experiment. The N-metabolism parameters such as protein synthesis and decomposition quotas were calculated on the basis of the temporal development of 15N-amounts excreted in urine. The labelling and reduction phases were evaluated simultaneously. By means of including the total N-amount of the animal body the balance calculation becomes more stable. The possible influence of the tracer amino acid in connection with the 3-pool-model is discussed on the basis of the ascertained parameters.

Animals↗
PubMed1975

Metabolism and mode of action of androgens in target tissues of male rats. V. Uptake and metabolism of cyproterone acetate and its influence on the uptake and metabolism of testosterone and 5alpha-dihydrotestosterone in target organs and peripheral tissues.

In order to get more information on the mode of action of anti-androgens, two series with low but biologically active doses of cyproterone acetate were started. In the first experiments 12 mug of [3H]cyproterone acetate was injected intravenously into adult rats castrated 3 days before treatment. Thirty min after injection the radioactivity uptake in the target organs and other tissues was measured. The metabolites were separated by thin layer chromatography. A large pool of radioactivity could be shown in the liver. Thin layer chromatography revealed that in this pool cyproterone acetate had been converted by more than 80% to one metabolite. In blood plasma, too, the metabolite accounted for the major part of radioactivity. When compared to skeletal muscle, the prostate, seminal vesicles, and m. bulbocavernosus and m. levator ani accumulated more radioactivity. Within 30 min unchanged cyproterone acetate was retained selectively thus showing its relative high affinity to target organs. In a second experimental series, adult castrated male rats were given 10 mug of cyproterone acetate intravenously 30 min before the injection of [3H]testosterone or [3H]5alpha-dihydrotestosterone. Under this condition androgen uptake in target tissues was reduced to about 70% of the control values. The data parallel the results of in vivo studies on cytosol receptor displacement of androgens by cyproterone acetate. In agreement with previous investigators no significant influence of the anti-androgen on androgen metabolism was observed. The importance of the findings concerning the mode of anti-androgen action is discussed.

Adipose Tissue↗
PubMed1999

The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine.

The selective serotonin reuptake inhibitor fluoxetine is administered as a racemic mixture, and R- and S-fluoxetine are metabolized in the liver by N-demethylation to R- and S-norfluoxetine, respectively. R- and S-fluoxetine and S-norfluoxetine are equally potent selective serotonin reuptake inhibitors, but R-norfluoxetine is 20-fold less potent in this regard. Racemic fluoxetine and norfluoxetine are potent inhibitors of cytochrome P450 (CYP) 2D6 in vivo and in vitro and recent studies in vivo have shown that racemic fluoxetine is metabolized by CYP2D6. The primary aim of the present study was to investigate the stereoselective metabolism of fluoxetine and norfluoxetine by CYP2D6 in vivo. A single oral dose of fluoxetine (60 mg) was administered to six poor and six extensive metabolizers of sparteine. Blood samples were collected during 6 weeks for poor metabolizers and 3 weeks for extensive metabolizers. Once a week a sparteine test was performed. The R- and S-enantiomers of fluoxetine and norfluoxetine were determined by a stereoselective gas chromatography-mass spectroscopy method. In the poor metabolizers, the oral clearance of R- and S-fluoxetine was 3.0 l/h and 17 l/h, respectively, the corresponding values in the extensive metabolizers were 36 l/h and 40 l/h, respectively. For both enantiomers, the phenotype difference was statistically significant. In poor metabolizers, the elimination half-lives were 6.9 days and 17.4 days for R- and S-norfluoxetine, respectively, and in the extensive metabolizers it was 5.5 days for both enantiomers, a significant phenotypical difference only for S-norfluoxetine. For fluoxetine the elimination half-lives were 9.5 and 6.1 days in poor metabolizers for the R- and S-enantiomer, respectively. The corresponding values in the extensive metabolizers were 2.6 and 1.1 days, respectively. Also for this parameter, the differences were statistically significant. This study shows that CYP2D6 catalyses the metabolism of R- and S-fluoxetine and most likely the further metabolism of S-norfluoxetine but not of R-norfluoxetine.

Area Under Curve↗
PubMed1997

Dose- and route-dependent alterations in metabolism and toxicity of chemical compounds in ethanol-treated rats: difference between highly (chloroform) and poorly (carbon tetrachloride) metabolized hepatotoxic compounds.

The dose and route dependency of the metabolism and the toxicity of chloroform (CHCl3) and carbon tetrachloride (CCl4) was investigated in ethanol-treated rats. Rats that had been kept on either an ethanol (containing ethanol at 2 g/rat/day) or a control (containing no ethanol) liquid diet for 3 weeks were challenged with CHCl3 or CCl4 by inhalation (0, 50, or 500 ppm x 6 hr), or by p.o. or i.p. administration (0, 0.105, or 1.675 mmol/kg). Ethanol consumption, which increased the in vitro metabolism of both compounds six- to sevenfold, affected the metabolism and toxicity of CCl4 differently from those of CHCl3. Ethanol increased the metabolism and toxicity of CHCl3 at 500 ppm only, whereas it increased the metabolism and toxicity of CCl4 at either 50 or 500 ppm. In addition, the effect of ethanol consumption differed between CHCl3 and CCl4 depending on the route of administration (p.o. or i.p.) and the dose (0.105 or 1.675 mmol/kg). For the p.o. route, ethanol increased the metabolism and toxicity of both compounds at either dose. For the i.p. route, however, ethanol increased the metabolism and toxicity of the high dose of CHCl3 only, but of both CCl4 doses. The dose- and route-dependent differences in the effect of enzyme induction on the metabolism and toxicity between CHCl3 and CCl4 can be explained by a supposition that the hepatic blood flow rate-limits the metabolism of a low dose of CHCl3 (perfusion-limited metabolism), whereas the metabolic capacity of the liver limits the metabolism of CCl4 (capacity-limited metabolism) irrespective of dose.

Administration, Inhalation↗
PubMed1993

Quantitative analysis of PET and MRI data in normal aging and Alzheimer's disease: atrophy weighted total brain metabolism and absolute whole brain metabolism as reliable discriminators.

Average whole brain metabolic rates, when corrected for brain atrophy, are similar between patients with Alzheimer's disease (AD) and age-matched controls. To elucidate the relationship between reduced cognitive function and cerebral metabolism in patients with AD, we hypothesized that the absolute amount of glucose used by the entire brain may prove to be a more reliable indicator of the disease than metabolic rates calculated for a unit of brain weight. Twenty patients with the probable diagnosis of AD and 17 similarly aged controls underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) studies as well as magnetic resonance imaging (MRI) within a few days of each other. Average metabolic rates, when corrected for atrophy, were 3.91 +/- 1.02 and 4.43 +/- 0.87 (mg of glucose per 100 cc brain tissue per min +/- s.d.) respectively for AD patients and controls. Two other indices were determined, atrophy weighted total brain metabolism (calculated by multiplying the brain volume, determined by MR analysis, by the average metabolic rate) and absolute whole brain metabolism (calculated by multiplying the brain volume by the average metabolic rate corrected for atrophy). The former showed a very significant difference between the two groups (29.96 +/- 7.90 for AD patients compared to 39.1 +/- 7.0 for controls, p < 0.001). Atrophy weighted total brain metabolism also correlated very well with mini mental status exam (MMSE) scores (r = 0.59, p < 0.01). Absolute whole brain metabolism was significantly different between AD and control groups and correlated well with MMSE. These data demonstrate that although the metabolic rate per unit weight of the brain is unchanged in AD compared to controls, atrophy weighted total brain metabolism and absolute whole brain metabolism are significantly affected. Both indices may prove to be a sensitive correlate for cognitive dysfunction in AD.

Aged↗
PubMed2005

Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis.

Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin II, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na+ reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin II and insulin in PTC may enhance hypertrophy of PTC and/or Na+ reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.

Diabetic Neuropathies↗
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↗
PubMed2006

Integrated analysis of metabolite and transcript levels reveals the metabolic shifts that underlie tomato fruit development and highlight regulatory aspects of metabolic network behavior.

Tomato (Solanum lycopersicum) is a well-studied model of fleshy fruit development and ripening. Tomato fruit development is well understood from a hormonal-regulatory perspective, and developmental changes in pigment and cell wall metabolism are also well characterized. However, more general aspects of metabolic change during fruit development have not been studied despite the importance of metabolism in the context of final composition of the ripe fruit. In this study, we quantified the abundance of a broad range of metabolites by gas chromatography-mass spectrometry, analyzed a number of the principal metabolic fluxes, and in parallel analyzed transcriptomic changes during tomato fruit development. Metabolic profiling revealed pronounced shifts in the abundance of metabolites of both primary and secondary metabolism during development. The metabolite changes were reflected in the flux analysis that revealed a general decrease in metabolic activity during ripening. However, there were several distinct patterns of metabolite profile, and statistical analysis demonstrated that metabolites in the same (or closely related) pathways changed in abundance in a coordinated manner, indicating a tight regulation of metabolic activity. The metabolite data alone allowed investigations of likely routes through the metabolic network, and, as an example, we analyze the operational feasibility of different pathways of ascorbate synthesis. When combined with the transcriptomic data, several aspects of the regulation of metabolism during fruit ripening were revealed. First, it was apparent that transcript abundance was less strictly coordinated by functional group than metabolite abundance, suggesting that posttranslational mechanisms dominate metabolic regulation. Nevertheless, there were some correlations between specific transcripts and metabolites, and several novel associations were identified that could provide potential targets for manipulation of fruit compositional traits. Finally, there was a strong relationship between ripening-associated transcripts and specific metabolite groups, such as TCA-cycle organic acids and sugar phosphates, underlining the importance of the respective metabolic pathways during fruit development.

Carbon↗
PubMed2001

Screening for inborn errors of metabolism among newborns with metabolic disturbance and/or neurological manifestations without determined cause.

CONTEXT: Inborn Errors of Metabolism are hereditary affections resulting from incompetence in enzymatic reactions of intermediary metabolism. At present, several hundred hereditary metabolic disturbances are known, many of which correspond to severe life-threatening disorders. OBJECTIVE: The early detection of carriers has motivated the screening for these disturbances among newborns at the Neonatal Unit of Hospital São Paulo, in an attempt to initiate support treatment, when available, before clinical manifestations become evident. DESIGN: Prospective study of risk patients. SETTING: Laboratory for Inborn Errors of Metabolism at the Center for Medical Genetics of the Departments of Pediatrics and Morphology of Universidade Federal de São Paulo/Escola Paulista de Medicina. Newborn care unit at a tertiary care hospital. PARTICIPANTS: 101 children admitted into the Neonatal Unit were included in this study by presenting hypoglycemia, metabolic acidosis, jaundice, difficulty in gaining weight, diarrhea, vomiting, hepato- and/or splenomegaly, cataracts, apnea, convulsions, hypo- or hypertonia. DIAGNOSTIC TESTS: Tests routinely utilized, performed for qualitative research of abnormal substances excreted in the urine in situations of metabolic disorder. RESULTS: Children were included in the study mainly because of presenting hypoglycemia, jaundice and metabolic acidosis. Sixty-four newborns presented at least one positive test result. Most of the positivity was due to transitory metabolic alterations of the newborn, such as the case of Transitory Neonatal Tyrosinemia, presented by 29 patients. Nine infants were referred to the Center for Medical Genetics of Universidade Federal de São Paulo for continuation of the diagnostic investigation. For three of them, the tests applied permitted us to formulate a diagnostic hypothesis of mucopolysaccharidosis, tyrosinemia type I and non-ketotic hyperglycinemia, respectively. CONCLUSIONS: The high positivity observed in the tests reflects the newborn's own metabolic immaturity. The selection of 9% of the studied cases for outpatient follow-up confirms that Inborn Errors of Metabolism must be suspected whenever a patient presents metabolic disturbances or neurological manifestations without a determined cause. They should be researched in parallel with the other diagnostic possibilities and not just taken to be exceptional diagnoses.

Female↗
PubMed2005

Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors, MPTP, and methamphetamine.

A number of strategies using the nutritional approach are emerging for the protection of the brain from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach that may prevent further damage. Various models have been developed to study the impact of metabolism on brain function. These have also proven useful in expanding our understanding of neurodegeneration processes. For example, the metabolic compromise induced by inhibitors such as 3-nitropropionic acid (3-NPA), rotenone, and 1-methyl-4-phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these models are thought to simulate the processes that may lead to diseases such as Huntington's and Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons. Various studies indicate that the neurotoxicity resulting from these types of metabolic compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic modifiers such as L-carnitine (L-C), creatine, and coenzyme Q10, as well as by antioxidants such as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may regulate membrane composition and influence cellular processes, especially the inflammatory pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L-C is a naturally occurring quaternary ammonium compound that is a vital cofactor for the mitochondrial entry and oxidation of fatty acids. Any factors affecting L-C levels may also affect ATP levels. This endogenous compound, L-C, together with its acetyl ester, acetyl-L-carnitine (ALC), also participates in the control of the mitochondrial acyl-CoA/CoA ratio, peroxisomal oxidation of fatty acids, and production of ketone bodies. A deficiency of carnitine is known to have major deleterious effects on the CNS. We have examined L-C and its acetylated derivative, ALC, as potential neuroprotective compounds using various known metabolic inhibitors, as well as against drugs of abuse such as methamphetamine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

What is the relationship between exercise and metabolic abnormalities? A review of the metabolic syndrome.

Prevention of the metabolic syndrome and treatment of its main characteristics are now considered of utmost importance in order to combat the epidemic of type 2 diabetes mellitus and to reduce the increased risk of cardiovascular disease and all-cause mortality. Insulin resistance/hyperinsulinaemia are consistently linked with a clustering of multiple clinical and subclinical metabolic risk factors. It is now widely recognised that obesity (especially abdominal fat accumulation), hyperglycaemia, dyslipidaemia and hypertension are common metabolic traits that, concurrently, constitute the distinctive insulin resistance or metabolic syndrome. Cross-sectional and prospective data provide an emerging picture of associations of both physical activity habits and cardiorespiratory fitness with the metabolic syndrome. The metabolic syndrome, is a disorder that requires aggressive multi-factorial intervention. Recent treatment guidelines have emphasised the clinical utility of diagnosis and an important treatment role for 'therapeutic lifestyle change', incorporating moderate physical activity. Several previous narrative reviews have considered exercise training as an effective treatment for insulin resistance and other components of the syndrome. However, the evidence cited has been less consistent for exercise training effects on several metabolic syndrome variables, unless combined with appropriate dietary modifications to achieve weight loss. Recently published randomised controlled trial data concerning the effects of exercise training on separate metabolic syndrome traits are evaluated within this review. Novel systematic review and meta-analysis evidence is presented indicating that supervised, long-term, moderate to moderately vigorous intensity exercise training, in the absence of therapeutic weight loss, improves the dyslipidaemic profile by raising high density lipoprotein-cholesterol and lowering triglycerides in overweight and obese adults with characteristics of the metabolic syndrome. Lifestyle interventions, including exercise and dietary-induced weight loss may improve insulin resistance and glucose tolerance in obesity states and are highly effective in preventing or delaying the onset of type 2 diabetes in individuals with impaired glucose regulation. Randomised controlled trial evidence also indicates that exercise training decreases blood pressure in overweight/obese individuals with high normal blood pressure and hypertension. These evidence-based findings continue to support recommendations that supervised or partially supervised exercise training is an important initial adjunctive step in the treatment of individuals with the metabolic syndrome. Exercise training should be considered an essential part of 'therapeutic lifestyle change' and may concurrently improve insulin resistance and the entire cluster of metabolic risk factors.

Cross-Sectional Studies↗
PubMed2000

Theory for the systemic definition of metabolic pathways and their use in interpreting metabolic function from a pathway-oriented perspective.

Cellular metabolism is most often described and interpreted in terms of the biochemical reactions that make up the metabolic network. Genomics is providing near complete information regarding the genes/gene products participating in cellular metabolism for a growing number of organisms. As the true functional units of metabolic systems are its pathways, the time has arrived to define metabolic pathways in the context of whole-cell metabolism for the analysis of the structural design and capabilities of the metabolic network. In this study, we present the theoretical foundations for the identification of the unique set of systemically independent biochemical pathways, termed extreme pathways, based on system stochiometry and limited thermodynamics. These pathways represent the edges of the steady-state flux cone derived from convex analysis, and they can be used to represent any flux distribution achievable by the metabolic network. An algorithm is presented to determine the set of extreme pathways for a system of any complexity and a classification scheme is introduced for the characterization of these pathways. The property of systemic independence is discussed along with its implications for issues related to metabolic regulation and the evolution of cellular metabolic networks. The underlying pathway structure that is determined from the set of extreme pathways now provides us with the ability to analyse, interpret, and perhaps predict metabolic function from a pathway-based perspective in addition to the traditional reaction-based perspective. The algorithm and classification scheme developed can be used to describe the pathway structure in annotated genomes to explore the capabilities of an organism.

Algorithms↗
PubMed1998

Metabolic activation of racemic and enantiomeric trans-8, 9-dihydroxy-8,9-dihydrodibenzo[a,l]pyrene (dibenzo[def,p]chrysene) to dibenzo[a,l]pyrene-bis-dihydrodiols by induced rat liver microsomes and a recombinant human P450 1A1 system: the role of the K-region-derived metabolic intermediates in the formation of dibenzo[a,l]pyrene-DNA adducts.

Metabolic activation studies of dibenzo[a,l]pyrene (DB[a,l]P) (dibenzo[def,p]chrysene), an extremely potent environmental carcinogen, have been focused on metabolism at the fjord region, a region associated with high mutagenic and carcinogenic activities of the corresponding fjord-region DB[a,l]P-11,12-diol-13,14-epoxides. DB[a,l]P is metabolized by beta-naphthoflavone (BNF)- and 3-methylcholanthrene-induced rat liver microsomes and a recombinant human P450 1A1 system to two major dihydrodiols, the K-region dihydrodiol, DB[a,l]P-8,9-dihydrodiol (DB[a,l]P-8,9-diol), and the fjord-region dihydrodiol, DB[a,l]P-11,12-dihydrodiol. We have investigated the further metabolic activation of DB[a,l]P-8,9-diol by BNF-induced rat liver microsomes and a recombinant human P450 1A1 system with epoxide hydrolase to DB[a,l]P-bis-diols and to DNA adducts. (+/-)-trans-DB[a,l]P-8,9-diol was synthesized and resolved into its enantiomers. Racemic trans-DB[a,l]P-8,9-diol was metabolized by BNF-induced rat liver microsomes to six metabolites: two diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol, two diastereomers of trans,cis-DB[a,l]P-8,9:11,12-bis-diol, and two diastereomers of trans-DB[a,l]P-8,9:13,14-bis-diol as characterized by NMR, MS, and UV spectroscopy. Metabolic studies using both enantiomeric (-)- and (+)-trans-DB[a,l]P-8,9-diol further demonstrated that each diastereomer of trans,trans-DB[a,l]P-8,9:11, 12-bis-diol and trans-DB[a,l]P-8,9:13,14-bis-diol was comprised of two enantiomers. Similarly, incubations of enantiomeric or racemic trans-DB[a,l]P-8,9-diol with a recombinant human P450 1A1 system and epoxide hydrolase also gave the same two enantiomeric mixtures of diastereomers of trans,trans-DB[a,l]P-8,9:11,12-bis-diol and the same two enantiomeric mixtures of diastereomers of trans-DB[a,l]P-8, 9:13,14-bis-diol. This suggested that the microsomal oxidations of (-)- and (+)-trans-DB[a,l]P-8,9-diol were stereospecific. The stereospecific formation of enantiomers of trans-DB[a,l]P-8,9-diol from DB[a,l]P was examined using both BNF-induced rat liver microsomes and a recombinant human P450 1A1 system with epoxide hydrolase. Stereospecificity was observed as both metabolic systems favored the formation of (-)-trans-DB[a,l]P-8,9-diol by 8-9-fold. DNA adduct studies were undertaken using TLC/HPLC 32P-postlabeling techniques. In the presence of a recombinant human P450 1A1 system with epoxide hydrolase, DB[a,l]P gave two groups of calf thymus DNA adducts. The group of later-eluting adducts were identified as arising from syn- and anti-DB[a,l]P-11,12-diol-13,14-epoxides, while the more polar early-eluting adducts were derived, in part, from the further activation of trans-DB[a,l]P-8,9-diol. Our data indicate that, in P450 1A1-mediated microsomal incubations, DB[a,l]P is metabolized to trans-DB[a,l]P-8,9-diol which is further metabolized to DB[a,l]P-bis-diols. trans-DB[a,l]P-8,9-diol is metabolically activated to intermediates that can bind to DNA and give DNA adducts similar to those observed with DB[a,l]P. These results indicate that DB[a,l]P can be metabolically activated by both fjord-region and K-region pathways.

Animals↗