Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

/pdf/glycolysis-inhibition-for-anticancer-treatment-40rjcq29jf.pdf

Glycolysis inhibition for anticancer treatment

WHO Guidelines for Indoor Air Quality: Selected pollutants.

Strategies such as genomics, proteomics and metabonomics are being applied with increasing frequency in the pharmaceutical industry. For each of these approaches, toxicological response can be measured by terms of deviation from control or baseline status. However, in order to accurately define drug-induced response, it is necessary to characterize the normal degree of physiological variation in the absence of stimuli. Here, 1H NMR spectroscopic-based analyses of the metabolic composition of urine in experimental animals under various normal physiological conditions are reviewed. In particular, the effects of inter-animal and diurnal variation, gender, age, diet, species, strain, hormonal status and stress on the biochemical composition of urine are explored. Pattern recognition methods facilitate the comparison of urine NMR spectra over a given time-course, enabling the establishment of changes in profile and highlighting the dynamic metabolic status of an organism. Thus metabonomic approaches based on information-rich spectroscopic data sets can be used to evaluate normal physiological variation and for investigation of drug safety issues.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/nbm.935

NMR‐based metabonomic approaches for evaluating physiological influences on biofluid composition

Some industrial chemicals

H2S (hydrogen sulfide) is a well known and pungent gas recently discovered to be synthesized enzymatically in mammalian and human tissues. In a relatively short period of time, H2S has attracted substantial interest as an endogenous gaseous mediator and potential target for pharmacological manipulation. Studies in animals and humans have shown H2S to be involved in diverse physiological and pathophysiological processes, such as learning and memory, neurodegeneration, regulation of inflammation and blood pressure, and metabolism. However, research is limited by the lack of specific analytical and pharmacological tools which has led to considerable controversy in the literature. Commonly used inhibitors of endogenous H2S synthesis have been well known for decades to interact with other metabolic pathways or even generate NO (nitric oxide). Similarly, commonly used H2S donors release H2S far too quickly to be physiologically relevant, but may have therapeutic applications. In the present review, we discuss the enzymatic synthesis of H2S and its emerging importance as a mediator in physiology and pathology. We also critically discuss the suitability of proposed 'biomarkers' of H2S synthesis and metabolism, and highlight the complexities of the currently used pharmacological H2S 'donor' molecules and 'specific' H2S synthesis inhibitors in their application to studying the role of H2S in human disease.

Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools.

1. The metabolism of 1-bromopropane in the rat has been re-investigated. The previously known metabolites have been isolated and confirmed as the three mercapturic acids N-acetyl-S-propyl cysteine, N-acetyl-S-propyl cysteine-S-oxide and N-acetyl-S-(2-hydroxypropyl)cysteine.2. Three further metabolites have been isolated from the urine of rats treated with 1-bromopropane. These have been identified as 3-bromopropionic acid and the mercapturic acids N-acetyl-S-(3-hydroxypropyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine.3. The metabolites of 3-bromopropanol and 3-chloropropanol in the rat have been shown to be the mercapturic acids N-acetyl-S-(3-hydroxypropyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine and the corresponding 2-carboxyethyl halide.4. Studies with 1-bromopropane and the 3-halopropanols in vitro indicate that oxidation of C3 and C2 of 1-bromopropane occurs before conjugation of the alkyl group with glutathione. The implications of these studies are discussed in relation to the mechani...

The Oxidative Metabolism of 1-Bromopropane in the Rat

1. The oxidative metabolism of [3-36Cl]chloropropan-1,2-diol (α-chloro-hydrin, I) was studied in male rats. Two metabolites were isolated and identified as β-chlorolactic acid (IV) and oxalic acid (V).2. Neither α-chlorohydrin nor β-chlorolactate was concentrated in any tissue. Traces of an intermediate metabolite, β-chlorolactaldehyde (III) were detected in the urine within 4 h of administration. Studies in vitro indicated that the metabolic pathway is: α-chlorohydrin, β-chlorolactaldehyde, β-chlorolactic acid.3. A comparative study of the metabolism of 36Cl- and 14C-β-chlorolactate showed that oxalate was produced slowly and, as calcium oxalate, caused a type of renal glomerular nephritis. This pathological condition is responsible for the diuretic action of both α-chlorohydrin and β-chlorolactate and, in higher doses, for their toxicities.4. The role of oxalate, as a metabolite of α-chlorohydrin and of a number of related compounds, in inducing the formation of spermatocoeles in the male rat reproducti...

The Oxidative Metabolism of α-Chlorohydrin in the Male Rat and the Formation of Spermatocoeles

1. The metabolism of several dihalopropanols has been studied in the rat. Irrespective of their structure, each compound produced the same two mercapturic acids, excreted as urinary metabolites.2. The mercapturic acid metabolites of the dihalopropanols were identified as N-acetyl-S-(2,3-dihydroxypropyl)cysteine and N, N-bis-acetyl-S, S'-(1,3-bis-cysteinyl)propan-2-ol. Depending on the halogen present, each dihalopropanol produced β-chlorolactate or β-bromolactate as oxidative metabolites.3. From the metabolic pathway of these compounds, it is inferred that an epoxide is an intermediate in their metabolism.4. The metabolism of 2-chloropropane-1, 3-diol has been investigated in the rat and the isolation of one mercapturic acid, N-acetyl-S-(2,3-dihydroxypropyl)cysteine, confirms that an epoxide intermediate is involved.

Epoxides as Obligatory Intermediates in the Metabolism of α-Halohydrins

1. The metabolism of 1,2-dichloropropane in the rat has been investigated. The major urinary metabolite has been isolated and identified as N-acetyl-S-(2-hydroxypropyl)cysteine. Two minor metabolites of 1,2-dichloropropane have been identified as β-chlorolactate and N-acetyl-S-(2,3-dihydroxypropyl)cysteine.2. The fate of 1-chloro-2-hydroxypropane, a proposed intermediate metabolite of 1,2-dichloropropane, has been investigated. Apart from its known urinary metabolite, N-acetyl-S-(2-hydroxypropyl)cysteine, two oxidative metabolites were detected. These were identified as β-chlorolactaldehyde and β-chlorolactate.3. A pathway is proposed for the metabolism and fate of 1,2-dichloropropane in the rat. This accounts for previous observations made for the fate of radioactivity from administration of 1,2-dichloro[1-14C]propane.4. The microbial and mammalian metabolism of several halogen-containing foreign compounds is discussed.

1,2-Dichloropropane: metabolism and fate in the rat.

1. The metabolism of [14C]formaldehyde has been investigated in the male Sprague-Dawley rat. It is extensively oxidized to CO2 and formate, which is excreted in the urine.2. Two radioactive compounds isolated from the urine of rats dosed with [14C]formaldehyde have been identified as N-hydroxymethylurea and N, N'-bis-(hydroxymethyl)urea, and shown to be urinary artefacts.3. Previous studies of the metabolism of formaldehyde by rats have been re-appraised. Differences in the rate of oxidation of formaldehyde in various strains of rats result in the excretion of different urinary metabolites and, in some cases, formaldehyde. Excretion of formaldehyde leads to the formation of several artefacts depending on the components present in the urine.

Formaldehyde metabolism by the rat: a re-appraisal.

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