Studies on the Regulation of Tyrosine Aminotransferase in Rats

Abstract

Abstract The kinetics of tyrosine-α-ketoglutarate aminotransferase induction and subsequent inactivation has been studied in individual animals by a serial liver biopsy technique. A 15-fold increase in enzyme activity followed the administration of cortisol (30 mg per kg) to adrenalectomized rats. Peak levels occurred about 6 to 7 hours after hormone injection. The induced tyrosine aminotransferase activity then rapidly subsided to basal levels, with a half-time of 1.7 hours. During this inactivation phase the liver was not refractory to further cortisol stimulation, since a second dose of hormone at this time was capable of initiating another induction cycle. Puromycin inhibited enzyme synthesis when it was given during the initial phase of induction. However, it unexpectedly caused a rapid reappearance of enzyme activity following its administration during the inactivation phase. This potentiated response is consistent with other observations which lead to the idea that a repressor is formed about 4 hours after hormone administration and that inhibition of repressor synthesis allows, at least temporarily, continued synthesis of enzyme. Puromycin had little effect on basal tyrosine aminotransferase levels, and these findings suggest that the turnover of the enzyme under basal conditions may be much slower than the rate of inactivation of the induced enzyme. Administration of actinomycin during the early stages of induction (1 to 3 hours after hormone injection) curtailed further enzyme synthesis and prevented inactivation of the enzyme already induced. However, administration of actinomycin during the latter phase of induction (inactivation phase) had little effect and did not prevent the disappearance of induced tyrosine aminotransferase activity. From these data it appears that an inactivating system is formed during the induction cycle which is responsible for the removal of the induced enzyme. This suggestion is supported by the finding that the enzyme is stable when liver slices are prepared early in the induction cycle, but disappears rapidly from slices removed during the latter phase of induction. Although the nature of the inactivator is not known, its effects are dependent on pituitary function, since adrenalectomized and hypophysectomized animals showed little or no inactivation phase following hormone administration.