USE OF TOP-DOWN ELASTICITY ANALYSIS TO IDENTIFY SITES OF THYROID HORMONE-INDUCED THERMOGENESIS

Top-down elasticity analysis is a novel extension of top-down metaboli c control analysis. It has provided researchers with a theoretical and practical platform upon which quantitative analyses of the sites of a ction of hormones and drugs can be based. This approach is easy to app ly and involves dividing up the metabolic system in question into two or three blocks of enzyme reactions around an intermediate between the blocks of reactions. The kinetic response of each block to the interm ediate is measured in the steady state in situ by determining the flux through the block at different measured intermediate concentrations. The intermediate can be manipulated by titrating the other blocks with suitable inhibitors or activators. Then, to determine which blocks of reactions are quantitatively the most important in terms of any chang e in the flux rate of the system, a quantitative comparison of the tit ration curves from the experimental preparations is made with those of the control preparations. In this minireview we will examine, as an e xample, the use of top-down elasticity analysis for the quantitative i dentification of the important sites of action of thyroid hormones on oxidative phosphorylation in hepatocytes. The experimental results sho w that approximately 50% of the change in resting oxygen consumption I n hepatocytes from hypothyroid and hyperthyroid rats (compared with eu thyroid controls) is attributable to changes in the rate of the mitoch ondrial proton leak; the remaining 50% is accounted for by changes in nonmitochondrial- and ATP turnover-dependent oxygen consumption in hyp othyroid and hyperthyroid hepatocytes, respectively..