THE REGULATION OF HEPATIC ENZYME ACTIVITY BY ADENOSINE TRIPHOSPHATE (ATP) EMMANUELFARBER, KENNETHH. SHULLand SAUL VILLA-TREVINO Department of Pathology, Universityof Pittsburgh School of Medicine Pittsburgh 13, Pennsylvania IT has become increasingly apparent during the past several years that the enzymatic complement is not a fixed property of a tissue but rather a very dynamic one, subject to wide variations under both normal and pathologic circumstances. Although all organs and tissues appear to take part in this cellular dynamism, the liver is probably the most labile. Large variations in the activities of many hepatic enzymes have been demonstrated during fasting, with changes in dietary composition or following the administration of various hormones. Although these studies have indicated something of the complexity and breadth of the problem of the regulation of enzyme activity in the liver, they have given few clues to the mechanisms under- lying this form of adaptation. Theoretically, at least three mechanisms may operate in regulating the metabolic activity of a cell. These are: (1) the levels of substrates available in the cell at any time, (2) the degree of activation or inhibition of the various components of an enzyme and (3) the balance between the rates of synthesis and the destruction of each enzyme com- ponent. The influence of substrate levels upon enzyme activities is now well substantiated.el)This maybe mediated either throughvariations in the degree of enzyme saturation or through inhibition or activation of an enzyme com- ponent. In one instance at least, that of tryptophan pyrrolase, the effect is in part the result of changes in enzyme synthesis. In the case of adrenal cortical hormones, it appears that they may regulate hepatic enzyme activity through an effect on protein synthesis. The mechanisms underlying variations in liver activities under pathologic circumstances are even more poorly understood than under physiologic. It is known that a wide variety of hepatic toxic agents may produce severe alterations in enzyme levels. Yet the mechanisms whereby these effects are brought about are not at all clear. Are they secondary to tissue des- truction or do many operate through the mechanisms which regulate the activity of the normal cell? In this discussion, I would like to present data suggesting the presence of two types of regulatory mechanisms in the liver 259