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Metabolic Consequences of a Reversed pH Gradient in Rat Tumors¹

Cancer Research Campaign Biomedical Magnetic Resonance Research Group, Division of Biochemistry, St. George's Hospital Medical School, London SW17 ORE, United Kingdom [M. S., L. R., F. A. H., J. R. G.], and Laboratory of Metabolism, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20892 [J. W., K-S. J., R. L. V.]

We have previously demonstrated (M. Stubbs, Z. M. Bhujwalla, G. M. Tozer, L. M. Rodrigues, R. J. Maxwell, R. Morgan, F. A. Howe, and J. R. Griffiths, NMR Biomed., 5: 351, 1992) that the intracellular pH (pH_i) of several rat tumors is higher (>pH 7.0) than that of the tumor extracellular fluid (pH_e), in contrast to normal tissues (e.g., liver) in which pH_i is lower than pH_e. In this paper we confirm a pH_e of 6.8 ± 0.07 (SEM) in Morris hepatoma 9618a by an independent method and report the tissue content of other ions by both ³¹P magnetic resonance spectroscopy and by conventional analysis in hepatomas and livers in rats. Compared with liver, tissue Na⁺ was 2-fold higher and tissue K⁺ was lower. Tissue Ca²⁺ was 8-fold higher (7.4 ± 4.3 µmol/g wet weight) and tissue P_i was 2-fold higher (8.5 ± 1.3 µmol/g wet weight) suggesting the presence of insoluble calcium phosphate. Cl^- was unchanged (40 µmol/g wet weight), whereas HCO^-₃ was lower in the hepatoma (12.4 ± 0.83 compared to 15.5 ± 0.76 µmol/g wet weight). Total tissue Mg²⁺ was similar in both tissues, but free [Mg²⁺] (calculated by two different methods) was 5-fold lower in the hepatoma. The ATP values were 3.5-fold and [NAD]/[NADH] 9-fold lower in the hepatoma. The results are compatible with the hypothesis that the chronic partial hypoxia of tumor tissue involves changes in the linked equilibria of many ions and metabolites and may help explain such pathologies as calcification.

¹ This research was supported in part by the United Kingdom Cancer Research Campaign.

² To whom requests for reprints should be addressed, at CRC Biomedical MR Group, Department of Cellular and Molecular Science, Cranmer Terrace, London SW 17 ORE, United Kingdom.

Received 12/ 1/93. Accepted 5/31/94.

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