Inhibition of Adrenal Steroidogenesis by Glutethimide

Johnston, G. Gilbert; Krisle, Joe R.; Troop, Robert C.

doi:10.3181/00379727-129-33239

Cited by 10 publications

(4 citation statements)

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“…Within 7 days, on a dose of t g/day, 15 healthy did not show any change in adrenal or pituitary reactivity (McMahon Sc Foley 1967). Yet, high concentrations of the drug were reported to inhibit adrenal cortex synthesis in the rat (Johnston et al 1968; Daniels-Severs Se Vernikos-Danellis 1973). These data and our findings regarding the in vitro inhibitory effect of glutethimide on animal and human adrenal suggest that patient intoxicated with the drug may have re¬ duced adrenal function.…”

Section: Discussionmentioning

confidence: 96%

Aminoglutethimide and Glutethimide: Effects on 18-Hydroxycorticosterone Biosynthesis by Human and Sheep Adrenals in Vitro

Touitou¹,

Bogdan²,

Legrand³

et al. 1975

Acta Endocrinologica

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The conversion of [1,2-3H] corticosterone to 18-hydroxycorticosterone in vitro was studied on human and animal adrenal tissue homogenates. Human adrenals were surgically resected from a patient with Cushing's disease. Sheep adrenal homogenates were prepared from the pooled glands of 20 animals. Incubations supplemented with a NADPH generating system were performed in order to evaluate the effect of aminoglutethimide and its closely related compound glutethimide on corticosterone 18-hydroxylation in vitro. Increasing concentrations of the two drugs were assayed on both human and animal adrenal homogenates. Aminoglutethimide was clearly found to inhibit corticosterone 18-hydroxylation in sheep adrenal homogenates as a 72.6 % inhibition occurred in the presence of only 0.2 \g=m\mole of the drug. Inhibition reached 91.1 % in the presence of 0.5 \g=m\moleaminoglutethimide. When added to the human incubated adrenal, a 59.4 % inhibition occurred in the presence of 0.5 \g=m\moleaminoglutethimide. Glutethimide, a sedative of wide clinical usage, was also found to inhibit corticosterone 18-hydroxylation but the inhibitory effect occurred only in the presence of much higher concentrations. In fact, 5.0 \g=m\moles were necessary to obtain a 43.9% inhibition of 18-hydroxycorticosterone synthesis.This study clearly demonstrates the marked inhibitory effect of aminoglutethimide on corticosterone 18-hydroxylation. Glutethimide, to a lesser extent, also inhibits 18-hydroxycorticosterone synthesis.

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Section: Discussionmentioning

confidence: 96%

Aminoglutethimide and Glutethimide: Effects on 18-Hydroxycorticosterone Biosynthesis by Human and Sheep Adrenals in Vitro

Touitou¹,

Bogdan²,

Legrand³

et al. 1975

Acta Endocrinologica

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“…Aminoglutethimide phosphate (Kahnt & Neher, 1966;Camacho et al, 1967;Wilroy et al, 1968;Johnston et al, 1968) and inhibitors of protein synthesis (Ferguson, 1963;Farese, 1964;Savard et al, 1965;Gorski & Padnos, 1966;Davis & Garren, 1968) prevent trophic stimulation of steroidogenesis in a wide variety of steroid-synthesizing tissues. To 1973 Table 3.…”

Section: Effects Of Cycloheximide and Aminoglutethimide Phosphate On mentioning

confidence: 99%

Control of ovarian cholesterol ester biosynthesis

Flint

Grinwich

Armstrong

1973

Biochemical Journal

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1. Experimental evidence is presented for a role of progesterone and 20alpha-hydroxypregn-4-en-3-one as inhibitors of cholesterol ester synthetase in the acute depletion of ovarian cholesterol ester after trophic stimulation. 2. Luteinizing hormone in vitro decreased by 84% the rate of esterification of cholesterol with added [(14)C]oleate by slices of rabbit ovarian interstitial tissue; this effect was mimicked by cyclic AMP (adenosine 3':5'-cyclic monophosphate) in vitro, and occurred without large changes in precursor pool sizes or membrane permeability. 3. Cyclic AMP was shown to have no direct effect on cholesterol ester synthetase or cholesterol esterase in cell-free extracts of rabbit ovarian interstitial tissue, but decreased the activity of cholesterol ester synthetase (not that of cholesterol esterase) in extracts prepared from slices previously incubated with it. 4. The inhibitory effect of cyclic AMP on esterification of cholesterol with added [(14)C]-oleate was prevented by both cycloheximide and aminoglutethimide phosphate (which also inhibited steroid synthesis in response to cyclic AMP). 5. Cyclic AMP raised the intracellular concentrations of progesterone and 20alpha-hydroxypregn-4-en-3-one in incubated slices by factors of 2.8 and 3.9 respectively. 6. Cycloheximide and aminoglutethimide phosphate administered in vivo blocked cholesterol ester depletion in response to luteinizing hormone in rats; in these ovaries cycloheximide and aminoglutethimide phosphate decreased the concentrations of progesterone and 20alpha-hydroxypregn-4-en-3-one and luteinizing hormone raised them. 7. Progesterone and 20alpha-hydroxypregn-4-en-3-one added to cell-free extracts of rabbit ovarian interstitial tissue in vitro (at concentrations comparable with those found in incubated slices) inhibited cholesterol ester synthetase by up to 85%. 8. The results are discussed with reference to the acute control of cholesterol ester concentrations in the ovary and adrenal cortex.

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“…The effects of glutethimide on steroidogenesis in the rat adrenal in vitro have been studied by Johnston, Krisle & Troop (1968). Relatively high concentrations (20-30 mg/100 g) of the drug were shown to inhibit corticosterone synthesis, this effect being demonstrable regardless of whether the glutethimide was administered to the rat prior to adrenalectomy or directly into the incubation fluid.…”

Section: Peripheral Metabolism Of Steroidsmentioning

confidence: 99%

Aminoglutethimide: a ‘side-effect’ turned to therapeutic advantage

Hughes¹,

Burley²

1970

Postgraduate Medical Journal

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SummaryAminoglutethimide was introduced as an anticonvulsant drug in the U.S. A. in 1960. The occurrence of a number of side-effects, including several endocrine effects such as goitrogenesis, sexual precocity and virilization, led to its withdrawal.Further investigation indicated that the drug inhibited adrenal biosynthesis, particularly of aldosterone, cortisol and androgens, probably by interfering with the conversion of cholesterol to delta-5-pregnenolone.Aminoglutethimide has also been shown to modify the extra-adrenal metabolism of cortisol.The possible clinical applications of these 'sideeffects' are discussed.

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Inhibition of Adrenal Steroidogenesis by Glutethimide

Cited by 10 publications

References 0 publications

Aminoglutethimide and Glutethimide: Effects on 18-Hydroxycorticosterone Biosynthesis by Human and Sheep Adrenals in Vitro

Aminoglutethimide and Glutethimide: Effects on 18-Hydroxycorticosterone Biosynthesis by Human and Sheep Adrenals in Vitro

Control of ovarian cholesterol ester biosynthesis

Aminoglutethimide: a ‘side-effect’ turned to therapeutic advantage

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