Leonard D. Garren

Evidence for the stimulation by adrenocorticotropic hormone of the conversion of cholesterol esters to cholesterol in the adrenal, in, vivo

Abstract Previous studies demonstrated that the inhibition of adrenal protein synthesis in vivo by cycloheximide blocked the ACTH ∗ stimulation of corticosterone secretion (Garren, Ney, and Davis, 1965) . It has been shown that cycloheximide acts by inhibiting the first step in the conversion of cholesterol to δ5-pregnenolone in the adrenal (Davis, Ney, and Garren, 1966 ; Davis and Garren 1966). The present study demonstrates that ACTH activates the conversion of adrenal cholesterol esters to free cholesterol even when adrenal protein synthesis and steroidogenesis are inhibited by cycloheximide.

MAMMALIAN ENZYME INDUCTION BY HYDROCORTISONE: THE POSSIBLE ROLE OF RNA.

Administration of hydrocortisone to rats resulted in an increase in the rate of synthesis of nuclear RNA in their livers. This effect was analysed by sedimentation studies of the rapidly labeled components in the liver nucleus and cytoplasm and also by studies of amino acid incorporation stimulated by liver nuclear RNA. It is concluded that the synthesis of various types of RNA, including messenger, are stimulated by the hormone. Simultaneous studies on hormone-induced changes in liver enzymes are compatible with these conclusions.

Contrasting effects of thyroxin on zoxazolamine and hexobarbital metabolism.

Abstract Administration of thyroxin to rats: (a) shortens the duration of action of zoxazolamine (2-amino-5-chlorobenzoxazole by accelerating its metabolism, and (b) prolongs the duration of action of hexobarbital by inhibiting its metabolism. Administration of the hormone does not alter the activity of the zoxazolamine-metabolizing enzyme system in liver microsomes, but does decrease the activity of the hexobarbital-metabolizing enzyme system in liver microsomes. Restricting the diet of the rats, so that their gain in weight was the same as the rats treated with thyroxin, inhibits the metabolism of hexobarbital, but does not alter the metabolism of zoxazolamine.

Puromycin analogs: action of adrenocorticotropic hormone and the role of glycogen.

The effect of the injection into rats of analogs of puromycin, 6-dimethylaminopurine, and the aminonucleoside of puromycin on the stimullation of steroidogenesis by adrenocorticotropic hormone was coin pared with that of puromycin and cycloheximide. This stimulation was blocked only by the antibiotics, which also inhibited adrenal protein synthesis. Glycogenolysis is not associated with the primary mechanism of the adrenocorticotropic hormone stimnulation of steroid hormone biosynthesis in rats.

A Study of the Mechanisms by Which Adrenocorticotropic Hormone Maintains Adrenal Steroidogenic Responsiveness

Following hypophysectomy in the rat, there was a progressive decline in the rate of adrenal protein synthesis in vivo during the ensuing 24-48 hr, and an accompanying decrease in the acute corticosterone secretory response to an intravenous injection of ACTH. There was a similar decrease in the in vitro conversion of Delta(5)-pregnenolone, progesterone, and deoxycorticosterone to corticosterone. These in vivo and in vitro effects of hypophysectomy could be reversed by the administration of depot ACTH for an additional 7 hr period. However, if cycloheximide, an inhibitor of protein synthesis, was administered concomitantly with the depot ACTH, then the restorative actions of ACTH on the steroid biosynthetic pathway were prevented. These experiments suggest that ACTH maintains not only the general structure of the adrenal cortex, but also the level of the steroid biosynthetic mechanism, through its effects on adrenal protein synthesis.