METABOLIC PATHWAYS IN THE INTACT LIVER CELL

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This project is a continuation of an attempt to map major metabolic pathways in the intact liver cell, including the processes of carbohydrate and lipid synthesis and degradation. We will explore the quantitative changes in the pathways which occur under conditions of addition of hormones such as glucagon, epinephrine and insulin; or addition of drugs of known or suspected clinical value; or of changes in composition and scheduling of diet. A numer of 1 4C and tritium labelled substrates will be used, and fitting of data to study state models will be carried out with the aid of a microcomputer. We will also attempt to localize the important control steps in these pathways: (a) by measuring changes in isotopic flux through the enzymes as affected by agents which increase or decrease the rate of the overall pathways; and (b) by the use of a new inhibitor titration technique. In this approach, in the ideal (i.e., assuming a perfect inhibitor), a given enzyme is subjected to a controlled, graded extent of inactivation, and the analysis of the effect on the overall pathway indicates whether the given step is an important (rate limiting) control step.