The Roles of Synthesis and Degradation in the Control of Rat Liver Tryptophan Pyrrolase

Abstract

It is now well established that in animal tissues a large number of enzyme activities can be increased by the administration of hormones (l-3), by specific substrates (1, 4), or by alterations in the nutritional state of the animal (58). In certain of these cases an increased content of newly synthesized enzyme protein has been shown to account for the increases in enzyme activity, as opposed to an activation phenomenon (9-12). Thus such changes in enzyme activity superficially resemble enzyme induction as observed in bacteria, the mechanism of which involves an increase in the differential rate of enzyme synthesis (13). An increased rate of synthesis has been shown to be responsible for the increases in rat liver tyrosine-glutamate transaminase (14) and glutamate-alanine transaminase (15) produced by corticosteroid administration. However, in view of the extensive and rapid replacement of liver proteins, i.e. turnover (16-20), a decrease in the rate of enzyme degradation can result equally well in the accumulation of enzyme. Recent studies from this laboratory have, in fact, shown that such a mechanism, i.e. enzyme stabilization, is important in regulating the level of arginase in rat liver (12). In this paper studies on the roles of both synthesis and degradation in controlling enzyme levels have been extended to rat liver tryptophan pyrrolase. Studies from various laboratories have indicated that tryptophan pyrrolase can be increased by the administration of either corticosteroids or tryptophan (1, 11, 21-24). Both agents produce an increased content of protein synthesized de nooo from amino acids, as indicated by studies with inhibitors of protein synthesis (21, 23, 24) and by specific immunological reactions (11). Nevertheless, certain studies have suggested that the corticosteroidand the tryptophan-mediated increases in tryptophan pyrrolase result from different mechanisms (22, 25). Inasmuch as tryptophan pyrrolase is rapidly degraded in viva (26, 27), an alteration in the rate of such degradation, as well as in the rate of enzyme synthesis, may be of significance in controlling the level of this enzyme. In a preliminary communication (27) we presented data suggesting that the administration of hydrocortisone to the intact rat increased the rate of synthesis of tryptophan pyrrolase, and that the administration of tryptophan decreased the rate of degradation of tryptophan pyrrolase. This evidence was based on the finding that the time courses of increase in tryptophan pyrrolase produced by repeated administrations of hydrocortisone or tryptophan, or both, were consistent with the time courses of increase predicted from a theoretical model if hydrocortisone increased the rate of synthesis 5to 7-fold, and if tryptophan decreased the rate of enzyme degradation essentially to zero (27). In the present paper these studies have been extended, and the results of data on the incorporation in viva of isotopic amino acids into, and loss from, tryptophan pyrrolase isolated by precipitation with specific antiserum are presented. These results indicate and confirm (27) that hydrocortisone increases the rate of tryptophan pyrrolase synthesis, and that tryptophan administration prevents the normally occurring, rapid degradation of the enzyme.