Metabolites were measured in freeze-clamped livers from rats that had been maintained for 3 weeks on a stock diet supplemented with 0.1 % 5,5'-diphenylthiohydantoin (DPTH). Compared with control animals, DPTH-treated animals had lower levels of phosphoenolypyruvate and 3-phosphoglycerate and elevated ratios of [ATP]/[ADP][Pi] and [NADP+]/[NADPH], suggesting mild hypothyroidism. Conversely, the administration of thyroxine (T4) for 5 days to animals fed the control diet resulted in elevated levels of phosphoenolpyruvate, 3-phosphoglycerate, and ketone bodies and lowered ratios of[ATP]/[ADP][Pi] and [NADP +]/[NADPH], consistent with the known effects of thyroid hormones on liver tissues. In animals simultaneously treated with DPTH and T4, the effects of thyroxine on the [NADP+]/[NADPH] ratio and the levels of phosphoenolypyruvate, 2-phosphoglycerate and ketone bodies were reversed. However, the calculated free cytoplasmic [ATP]/[ADP][Pi] ratio and the calculated cytochrome c3+/cytochrome C2+ ratio did not return to control values. This suggests that those actions of thyroid hormone which are mediated by potentiation of adrenergic effects are reversed by DPTH. These actions include a decrease in peripheral lipolysis, a reduction of the free cytoplasmic [NADP+]/[NADPH] ratio, and an apparent inhibition of the pyruvate kinase reaction, but DPTH apparently does not reverse the effects of thyroid hormone on mitochondrial 02 consumption and A TP generation.
Get full access to this article
View all access options for this article.
References
1.
Bargoni, N., Grillo, M.A., Rinaudo, M.T. and Foss, T. (1968). Uber den Kohlenhydrat-Stoffwechsel in der Leber und der Niere von mit Propylthiouracil oder Schilddrüse gefütterten Ratten. Hoppe-Seylvers, Z. Physiol. Chem.349:275-278.
2.
Biron, R., Burger, A., Chinet, A., Clausen, T. and Dubois-Ferriere, R. (1979). Thyroid hormones and the energetics of active sodium-potassium transport in mammalian skeletal muscles. J. Physiol.297:47-60.
3.
Bronk, J.R. and Bronk, M.S. (1962). The influence of thyroxine on oxidative phosphorylation in mitochondria from thyroidectomized rats. J. Biol. Chem.287:897-903.
4.
Chan, T.M. and Exton, J.H. (1978). Studies on β-adrenergic activation of hepatic glucose output. J. Biol. Chem.253:6343-6400.
5.
Colton, D.G., Mehlman, M.A. and Ruegamer, W.R. (1972). Effect of thyroxine and 5,5'-diphenyl-2-thiohydantoin on enzyme activities of rat liver and kidney. Endocrinology90:1521-1528.
6.
Debons, A.F. and Schwartz, I.L. (1961). Dependence of the lipolytic action of epinephrine in vitro upon thyroid hormone. J. Lipid Res.2:86-89.
7.
Fairhurst, A.S., Roberts, J.C. and Smith, R.E. (1959). Effects of physiological levels of thyroxine in vivo on respiration and phosphorylation in rat liver fractions. Am. J. Physiol.197:370-376.
8.
Folke, M. and Sestoft, L. (1977). Thyroid calorigenesis in isolated, perfused rat liver: minor role of active sodium-transport. J. Physiol.269:407-419.
9.
Foster, J.L. and Blair, J.B. (1978). Acute hormonal control of pyruvate kinase and lactate formation in the isolated rat hepatocyte. Arch. Biochem. Biophys.189:263-276.
10.
Garrison, J.C. and Borland, M.K. (1979). Regulation of mitochondrial pyruvate carboxylation and gluconeogenesis in rat hepatocytes via an alpha-adrenergic, adenosine 3':5' mono-phosphate-independent mechanism. J. Biol. Chem.254:1129-1133.
11.
Guynn, R.W., Veloso, D. and Veech, R.L. (1972). Enzymic determination of inorganic phosphate in the presence of creatine phosphate. Anal. Biochem.45:277-285.
12.
Hems, R., Ross, B.D., Berry, M.N. and Krebs, H.A. (1966). Gluconeogenesis in the perfused liver. Biochem. J.101:284-292.
13.
Himms-Hagen, J. (1972). Effects of catecholamines on metabolism. In: Handbook of Experimental Pharmacology ( Blaschko, H. and Muscholl, E. eds.). Catecholamines 33:363-462, Springer-Verlag , Berlin.
14.
Hoch, F.L. and Lipmann, F. (1954). Uncoupling of respiration and phosphorylation by thyroid hormones. Proc. Natl. Acad. Sci. U.S.A. 40:909-921.
15.
Ismail-Beigi, F. and Edelman, I.S. (1970). Mechanism of thyroid calorigenesis: role of active sodium transport. Proc. Natl. Acad. Sci. U.S.A.67:1071-1078.
16.
Krishna, G., Hyniem, S. and Brodie, B.B. (1968). Effects of thyroid hormones on adenyl cyclase in adipose tissue and on free fatty acid mobilization. Proc. Natl. Acad. Sci. U.S.A.59:884-889.
17.
Lardy, H.A. and Feldhoff, G. (1951). Metabolic effects of thyroxine in vitro. Ann. N.Y. Acad. Sci.54:531-536.
18.
Londesborough, J.C. and Dalziel, K. (1968). The equilibrium constant of the isocitrate dehydrogenase reaction. Biochem. J.110:217-222.
19.
Lowry, O.H. and Passonneau, J.V. (1972). A Flexible System of Enzymatic Analysis, New York, Academic Press , 1972.
20.
Mehlman, M.A., Tobin, R.B., Ruegamer, W.R. and Madappally, M.W. (1972). Mode of action of 5,5'-diphenylthiohydantoin - Sites of action in mitochondria in relationship to thyroxine-stimulated responses. Biochem. Pharmacol.21:2031-2042.
21.
Nishiki, K., Erecinska, M., Wilson, D.F., and Cooper, S. (1978). Evaluation of oxidative phosphorylation in hearts from euthyroid, hypothyroid rats. Am. J. Physiol. 235:C212-C219.
22.
Schaffer, W.T., Denckla, W.D. and Veech, R.L. (1980). The effects of chronic ethanol consumption on the rate of whole animal and perfused liver oxygen consumption. In: Alcohol and Aldehyde Metabolizing Systems ( Thurman, R.G. ed.), Vol. 4, Plenum Publishing Company, New York, pp 587-593.
23.
Spry, M.S. (1971). Relationship between the redox state of the pyridine nucleotides, the phosphorylation state of the adenine nucleotides and substrate utilization in animal tissues. BS Thesis, Oxford University .
24.
Surks, M.I. and Oppenheimer, J.H. (1977). Concentration of L-thyroxine and L-triiodothyronine specifically bound to nuclear receptors in rat liver and kidney. J. Clin. Invest.60:555-562.
25.
Tata, J.R., Ernster, L. and Lindberg, O. (1962). Control of basal metabolic rate by thyroid hormones and cellular function. Nature193:1058-1060.
26.
Tobin, R.B., Berdanier, C.D. and Enklund, R.E. (1979a). Effect of L-thyroxine treatment on the levels of various hepatic metabolites in rats. J. Environ. Pathol. Toxicol.2:1223-1234.
27.
Tobin, R.B., Berdanier, C.D. and Enklund, R.E. (1979b). Effects of thyroxine treatment on the hepatic plasma membrane ATPase activity in rats. J. Environ. Pathol. Toxicol.2:1935-1945.
28.
Tsukui, T., Aizawa, T., Yamada, T. and Kawabem, T. (1978). Studies on the mechanism of goitrogenic action of diphenylthiohydantoin. Endocrinology102:1662-1669.
29.
Veech, R.L., Cook, G.A. and King, M.T. (1980). Relationship of free cytoplasmic pyrophosphate to liver glucose content and total pyrophosphate to cytoplasmic phosphorylation potential. FEBS Lett.117 (suppl.):K65-K72.
30.
Veech, R.L., Guynn, R. and Veloso, D. (1972). The time course of the effects of ethanol on the redox and phosphorylation states of rat livers. Biochem. J.127:387-397.
31.
Veech, R.L., Lawson, J.W.R., Cornell, N.W. and Krebs, H.A. (1979). Cytosolic phosphorylation potential. J. Biol. Chem.254:6538-6547.
32.
Veech, R.L., Nielsen, R. and Harris, R.L. (1975). Effects of pineal and other hormones on the free [NADP+]/[NADPH] ratio in rat liver. In: Frontiers of Pineal Physiology (Altschule, M.D. ed.), pp. 177-196, M.I.T. Press, London.
33.
Williamson, D.H., Lund, P. and Krebs, H.A. (1967). The redox state of free nicotinamide-adenine dinucleotidie in the cytoplasm and mitochondria of rat liver. Biochem. J.103:514-527.
34.
Wilson, D.F., Stubbs, M., Veech, R.L., Erecinska, M. and Krebs, H.A. (1974a). Equilibrium relations between the oxidation-reduction reaction and the adenosine triphosphate synthesis in suspensions of isolated liver cells. Biochem. J.140:57-64.
35.
Wilson, D.F., Stubbs, M., Oshino, N. and Erecinska, M. (1974b). Thermodynamic relationships betweeen the mitochondrial oxidation-reduction reactions and the cellular ATP levels in Ascites tumor cells and perfused rat liver. Biochemistry13:5303-5311.
36.
Young, J.W. (1968). Effects of d- and 1-thyroxine on enzymes in liver and adipose tissue of rats. Am. J. Physiol.214:378-383.
