A p.m.r. isotope-exchange method for studying the kinetic properties of dehydrogenases in intact cells

Simpson, Robert J.; Brindle, Kevin M.; Brown, Francis F.; Campbell, Iain D.; Foxall, David L.

doi:10.1042/bj2020573

Cited by 42 publications

(20 citation statements)

References 23 publications

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“…Only small hyperpolarized [1-13 C]lactate signals were observed in muscle (3), consistent with the fact that resting muscle has low levels of lactate. Similarly, despite that fact that red blood cells are known to have relatively high LDH activity (15,27), only limited lactate labeling was observed in the blood pool (3,28), implying again that there is limited lactate available for exchange.…”

Section: Discussionmentioning

confidence: 99%

“…Imaging of the whole exchange time course, however, is technically challenging due to continuous loss of polarization. Moreover, possible changes in the pyruvate and lactate concentrations during the exchange time course will result in changes in the exchange rate constants as the degree of saturation of the enzyme with its substrates changes (15)(16)(17). Therefore, we also assessed the capability of magnetization transfer experiments to give more rapid estimates of the exchange rate constants.…”

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confidence: 99%

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Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

et al. 2010

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Measurements of the conversion of hyperpolarized [1-13 C]pyruvate into lactate, in the reaction catalyzed by lactate dehydrogenase, have shown promise as a metabolic marker for the presence of disease and response to treatment. However, it is unclear whether this represents net flux of label from pyruvate to lactate or exchange of isotope between metabolites that are close to chemical equilibrium. Using saturation and inversion transfer experiments, we show that there is significant exchange of label between lactate and pyruvate in a murine lymphoma in vivo. The rate constants estimated from the magnetization transfer experiments, at specific points during the time course of label exchange, were similar to those obtained by fitting the changes in peak intensities during the entire exchange time course to a kinetic model for two-site exchange. These magnetization transfer experiments may therefore provide an alternative and more rapid way of estimating flux between pyruvate and lactate to serial measurements of pyruvate and lactate 13 C peak intensities following injection of hyperpolarized [1-13 C]pyruvate. Magn Reson Med 63:872-880,

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

et al. 2010

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“…This is not too surprising, because the equilibrium favors lactate. However, it is also well established that lactate and pyruvate are in rapid exchange under equilibrium conditions (Day et al , 2007; Simpson et al , 1982; Xu et al , 2007). Independent of the balance between net flux and exchange, the level of 13 C-lactate observed in hyperpolarized 13 C-pyruvate studies, at least in other tissues, has been linked to several important changes in metabolic state, such as correlations of the 13 C-lactate signal with lactate dehydrogenase activity (Ward et al , 2010), disease progression (Albers et al , 2008), and changes in redox state, NAD/NADH, caused by alcohol consumption (Spielman et al , 2009).…”

Section: Discussionmentioning

confidence: 99%

Cerebral Dynamics and Metabolism of Hyperpolarized [1-¹³C]pyruvate Using Time-Resolved MR Spectroscopic Imaging

Hurd

Yen

Tropp

et al. 2010

J Cereb Blood Flow Metab

102

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Dynamic hyperpolarized [1-13 C]pyruvate metabolic imaging in the normal anesthetized rat brain is demonstrated on a clinical 3-T magnetic resonance imaging scanner. A 12-second bolus injection of hyperpolarized [1-13 C]pyruvate is imaged at a 3-second temporal resolution. The observed dynamics are evaluated with regard to cerebral blood volume (CBV), flow, transport, and metabolic exchange with the cerebral lactate pool. A model for brain [1-13 C]lactate, based on blood-brain transport kinetics, CBV, and the observed pyruvate dynamics is described.

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“…Increasing the pyruvate concentration might be expected to increase the exchange velocity; however, this effect will be offset to some extent by a decrease in the equilibrium concentration of NADH, which will tend to decrease the exchange velocity (71,72).…”

Section: Net Flux or Exchange? Understanding Hyperpolarized Substratementioning

confidence: 99%

Tumor imaging using hyperpolarized ¹³C magnetic resonance spectroscopy

Brindle¹,

Bohndiek²,

Gallagher³

et al. 2011

Magnetic Resonance in Med

236

355

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Dynamic nuclear polarization is an emerging technique for increasing the sensitivity of magnetic resonance imaging and spectroscopy, particularly for low-g nuclei. The technique has been applied recently to a number of 13 C-labeled cell metabolites in biological systems: the increase in signal-to-noise allows the spatial distribution of an injected molecule to be imaged as well as its metabolic product or products. This review highlights the most significant molecules investigated to date in preclinical cancer models, either in terms of their demonstrated metabolism in vivo or the biological processes that they can probe. Key words: hyperpolarized carbon-13; dynamic nuclear polarization; imaging; metabolism; tumor; pyruvateThe application of magnetic resonance in medicine has been dominated by imaging of tissue anatomy. However, one of the great strengths of magnetic resonance (MR) is spectroscopy, which allows imaging of tissue biochemistry; this was recognized in the earliest applications of MR to intact biological systems (1). Although magnetic resonance imaging (MRI) has become a routine clinical tool, the use of magnetic resonance spectroscopy (MRS) in patients has lagged far behind; this has been primarily due to a lack of sensitivity, which leads to long measurement times and poor image resolution (2-5). In spite of this, 1 H-MRS measurements of cellular metabolites in a variety of tumor types have been shown to provide a sensitive means to diagnose disease and detect response to treatment (2-4). However, these measurements generally give a static picture of cellular metabolism.In contrast, 13 C-MRS measurements of cellular metabolism in systems incubated with 13 C-labeled cell substrates give a dynamic, and therefore potentially more useful, measurement of tissue metabolism (6-8). For example, dynamic measurements of 13 C-labeled glucose incorporation into muscle glycogen have been used to dissect the relative importance of glucose transport and hexokinase and glycogen synthase activity in controlling muscle glycogen synthesis (9). However, the problem of low sensitivity is even more acute in the case of 13 C-MRS. Dynamic nuclear polarization (DNP or hyperpolarization) of 13 C-labeled cell substrates enhances their sensitivity to detection by >10 4 -fold (10,11). Subsequent spectroscopic imaging of their metabolism following intravenous injection offers a solution to the problem of low sensitivity and has the potential to make dynamic metabolic imaging using MRS a routine clinical application.There have been a number of recent review articles and book chapters on this subject (12-17), and therefore, the purpose of this brief review is to: highlight those DNP substrates that have shown the greatest promise for oncological applications in vivo; summarize the biochemical mechanisms responsible for label transfer from pyruvate to other metabolites in tumors; and finally provide an overview of the main challenges in label detection and imaging and how these may be addressed. PROMISING SUBSTRATES FOR HYPERPOLA...

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A p.m.r. isotope-exchange method for studying the kinetic properties of dehydrogenases in intact cells

Cited by 42 publications

References 23 publications

Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

Cerebral Dynamics and Metabolism of Hyperpolarized [1-¹³C]pyruvate Using Time-Resolved MR Spectroscopic Imaging

Tumor imaging using hyperpolarized ¹³C magnetic resonance spectroscopy

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A p.m.r. isotope-exchange method for studying the kinetic properties of dehydrogenases in intact cells

Cited by 42 publications

References 23 publications

Magnetization transfer measurements of exchange between hyperpolarized [1-13C]pyruvate and [1-13C]lactate in a murine lymphoma

Magnetization transfer measurements of exchange between hyperpolarized [1-13C]pyruvate and [1-13C]lactate in a murine lymphoma

Cerebral Dynamics and Metabolism of Hyperpolarized [1-13C]pyruvate Using Time-Resolved MR Spectroscopic Imaging

Tumor imaging using hyperpolarized 13C magnetic resonance spectroscopy

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Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

Magnetization transfer measurements of exchange between hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate in a murine lymphoma

Cerebral Dynamics and Metabolism of Hyperpolarized [1-¹³C]pyruvate Using Time-Resolved MR Spectroscopic Imaging

Tumor imaging using hyperpolarized ¹³C magnetic resonance spectroscopy