Metabolic control mechanisms in mammalian systems. Involvement of adenosine 3′:5′-cyclic monophosphate in androgen action

Abstract

1. The ability of exogenously administered cyclic AMP (adenosine 3':5'-monophosphate) to exert andromimetic action on certain carbohydrate-metabolizing enzymes was investigated in the rat prostate gland and seminal vesicles. 2. Cyclic AMP, when injected concurrently with theophylline, produced marked increases in hexokinase, phosphofructokinase, glyceraldehyde phosphate dehydrogenase, pyruvate kinase, and two hexose monophosphate-shunt enzymes, as well as alpha-glycerophosphate dehydrogenase activity in accessory sexual tissues of castrated rats. The 6-N,2'-O-dibutyryl analogue of cyclic AMP caused increases of enzyme activity that were greater than those induced by the parent compound. 3. Time-course studies demonstrated that, whereas significant increases in the activities of most enzymes occurred within 4h after the injection of cyclic AMP, maximal increases were attained at 16-24h. 4. Increase in the activity of the various prostatic and vesicular enzymes was dependent on the dose of cyclic AMP; in most instances, 2.5mg of the cyclic nucleotide/rat was sufficient to elicit a statistically significant response. 5. Administration of cyclic AMP and theophylline also produced stimulation of enzyme activities in secondary sexual tissues of immature rats. 6. Cyclic AMP and theophylline did not affect significantly any of the enzymes studied in hepatic tissue. 7. Stimulation of various carbohydrate-metabolizing enzymes in the prostate gland and seminal vesicles by cyclic AMP was independent of adrenal function. 8. Concurrent treatment with actinomycin or cycloheximide prevented the cyclic AMP- and theophylline-induced increases in enzyme activities in both castrated and adrenalectomized-castrated animals. 9. Administration of a single dose of testosterone propionate (5.0mg/100g) to castrated rats caused a significant increase in cyclic AMP concentration in both accessory sexual tissues. 10. In addition, treatment with theophylline potentiated the effects of a submaximal dose of testosterone (1.0mg/100g) on all those prostatic and seminal-vesicular enzymes that are increased by exogenous cyclic AMP. 11. The evidence indicates that cyclic AMP may be involved in triggering the known metabolic actions of androgens on secondary sexual tissues of the rat.

Messenger Ribonucleic Acid of Rat Testicular Retinoic Acid Receptors: Developmental Pattern, Cellular Distribution, and Testosterone Effect1

“…It was reported that cAMP analogues inhibited the expression of mRNAs for RARo, -, and -y in F9 teratocarcinoma cells [29]. Since testosterone had been reported to stimulate adenyl cyclase activity in prostate glands of castrated rats [30], and cAMP levels in testes of hypophysectomized rats [31] and in rat seminal vesicles cultured in vitro [32], the suppression of RARy mRNA following testosterone administration may result from an increase of testicular cAMP. The increase in the RARa mRNA, on the other hand, perhaps reflects the net balance between the putative cAMP-mediated inhibitory effect and certain unidentified stimulatory mechanisms that apparently were absent or less effective in the expression of RARy mRNA.…”

Molecular Mechanism of Action of the Male Sex Hormones

“…We assume that this is the general case for all the tissues that are metabolically dependent on androgens; however, it is also possible that in some instances characteristics of the cell membrane determine the extent of entry. In this respect it is important to recall the involvement of cyclic AMP in androgen action in the secondary sexual tissues of the rat (Rosenfeld & O'Malley, 1970;Singhal et al 1971 ;Mangan, Pegg & Mainwaring, 1973). Once the androgen is inside the cell, it is subjected to extensive metabolic conversions.…”

MECHANISM OF OESTRADIOL ACTION ON THE RAT UTERUS: INDEPENDENCE OF CYCLIC AMP, PROSTAGLANDIN E2 AND Β-Adrenergic MEDIATION

“…The present study throws doubt on part of this interesting hypothesis, since we failed to elicit a rise in uterine cyclic AMP production by oestradiol treatment, and have also failed to demonstrate any increase in uterine protein kinase activity within 4 h of a sub¬ cutaneous injection of 5 fig oestradiol-11 ß in immature rats (unpublished observa-37-2 tions). Singhal & Lafreniere (1972) propose, on different grounds (see Introduction), that cyclic AMP plays an important role in triggering all the known metabolic effects of oestrogens on the uterus. Our findings do not support this conclusion.…”

“…These results led Szego & Davis (1967), Szego (1972 and Singhal & Lafreniere (1972) to propose that the adenyl cyclase-cyclic AMP system of the cell membrane, and possibly /i-adrenergic receptors (Szego & Davis, 1969a), may be implicated in the mediation of the earliest effects of oestradiol on the uterus. On the other hand, it is widely believed that the primary interaction of oestradiol in target organs is with a cytoplasmic receptor protein (Noteboom & Gorski, 1965;King & Gordon, 1966;Jensen, Suzuki, Kawashima, Stumpf, Jungblut & DeSombre, 1968).…”

“…injection of diethylstilboestrol into ovariectomized rats. Furthermore, Hechter, Yoshinaga, Halkerston & Birchall (1967) showed that exo¬ genous cyclic AMP mimicked the anabolic effects of oestradiol on the rat uterus in vitro with respect to RNA, protein, lipid and glycogen synthesis (see also Sharma & Talwar, 1970;Rao & Talwar, 1972;Singhal & Lafreniere, 1972) and Griffin & Szego (1968) obtained stimulation of uterine amino acid uptake in vitro by cyclic AMP.…”