Metabolism of 17α-Methylandrostenediol and 17α-Methyltestosterone by the Rat Adrenal Glandin Vitro

Rembiesa, R; Holzbauer, Margarethe; Young, Peter; Birmingham, Marion K.; Saffran, Murray

doi:10.1210/endo-81-6-1278

Cited by 15 publications

(2 citation statements)

References 7 publications

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“…adrenal homogenates did not inhibit the conversion of progesterone to corticosterone (2). In addition, it has been shown that rat adrenal tissue oxidizes MAD to MT (5). These latter observations are consistent with the concept that treatment of rats with MAD leads to inhibition of corticosterone formation by a mechanism involving conversion of the MAD to MT and the competitive inhibition of 11/3-hydroxylation of DOC by the MT.…”

supporting

confidence: 84%

Some Studies on the Effect of Androgens on Adrenal Cortical Function of Rats

et al. 1970

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The effect of ACTH upon the inhibition of corticosteroidogenesis produced by treating rats with several synthetic adrogens has been evaluated. In experiments lasting about 2 weeks in which the simultaneous treatment with ACTH prevented the fall in adrenal weight due to the androgen therapy, corticosteroidogenesis measured in adrenal homogenates was still greatly reduced. Associated with the reduced production of corticosterone from progesterone there was a marked fall in the level of adrenal mitochondrial cytochrome P-450. The fall in cytochrome P-450 was not prevented by simultaneous treatment with ACTH. Treatment of rats with all 3 androgens, 17a-methylandrostenediol, 17a-methyltestosterone and 11/3-hydroxy-17«-methyltestosterone, brought about the decrease in cytochrome P-450 levels, whereas when metyrapone, a nonsteroidal competitive inhibitor of steroid 11/3-hydroxylase, was given to rats for 6 weeks no change occurred in the level of adrenal mitochondrial cytochrome P-450. These data suggest that this property of the androgens is not necessarily related to their potential as inhibitors of steroid hydroxylases. {Endocrinology 86: 1085, 1970)

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confidence: 84%

Some Studies on the Effect of Androgens on Adrenal Cortical Function of Rats

et al. 1970

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“…In addition, Brownie and Skelton* found that steroid 11/8-hydroxylase activity was low in adrenal homogenates and mitochondria from MAD-treated rats, leading to an accumulation of 11-deoxycorticosterone (DOC). MAD is converted to 17a-methyltestosterone (MT; 17a-methyl-4-androstene-17/3-ol-3-one) in the adrenal 4 and MT is similar to testosterone' in being an inhibitor of the 11/3-hydroxylation of DOC." This has led to general agreement that increased secretidn of the hypertensinogenic steroid DOC 7 is involved in the pathogenesis of MADinduced hypertension.…”

Section: S Keltonmentioning

confidence: 99%

Peripheral serum corticosteroid concentrations in relation to the rat adrenal cortical circadian rhythm in androgen-induced hypertension.

Fink¹,

Gallant²,

Brownie³

1980

Hypertension

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SUMMARY Adrenal function was assessed in control rats and in rats treated for 2 and 4 weeks with 17a-methylandrosteriediol (MAD; 17a-methyl-5-androstene-30,170-diol), a synthetic androgen known.to produce hypertensive cardiovascular disease. In both groups and at both time periods, a circadian rhythm of blood corticosteroid concentrations was observed. The high point for serum corticosterone (B), 18-hydroxy-lldeoxycordcosterone (18-hydroxy-DOC), and 11-deoxycorticosterone (DOC) concentrations occurred at the beginning of the dark period (1800 hours), and the low point occurred at the onset of the light period (0600 hours). Serum concentrations of DOC were always found to be higher in MAD-treated rats as compared with controls. The serum concentrations of B and 18-hydroxy-DOC were lower than control values at 1800 hours but higher than control concentrations at 0600 hours. The in vitro 11/3-and 18-hydroxylation of DOC was markedly reduced with MAD treatment. In contrast, cholesterol side-chain cleavage activity was higher in animals treated with MAD. These in vitro findings correlated with spectral studies that showed a decreased binding of DOC to cytochrome P45O 1U and increased binding of cholesterol to cytochrome P450^x. These studies suggest that MAD treatment selectively decreases 11/9-and 18-hydroxylatlon in adrenal mitochondria, and this results in an increased serum concentration of DOC, a hypertensinogenic steroid. This effect of MAD on peripheral serum DOC concentration is most readily observed in quiescent animals at the high point of the circadian rhythm.

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Male Sex Hormones, Analogs, and Antagonists

Brueggemeier

2010

Burger's Medicinal Chemistry and Drug Discovery

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The steroid testosterone is the major circulating sex hormone of the male and serves as the prototype for the androgens, the anabolic agents, and androgen antagonists. The endogenous androgens are biosynthesized from cholesterol in various tissues in the body; the majority of the circulating androgens are made in the testes under the stimulation of the gonadotropin luteinizing hormone ( LH ). The reduction of testosterone to dihydrotestosterone is necessary for the androgenic actions of testosterone in many androgen target tissues such as the prostate; the oxidation of testosterone by the enzyme aromatase produces estrogens. The androgenic actions of testosterone and dihydrotestosterone are due to their binding to the androgen receptor, followed by nuclear localization, dimerization of the receptor complex, and binding to a specific DNA sequence. This binding of the homodimer to the androgen response element leads to gene expression, stimulation or repression of the synthesis of new mRNA, and subsequent protein biosynthesis. The synthetic androgens and anabolics were prepared to impart oral activity to the androgen molecule, to separate the androgenic effects of testosterone from its anabolic effects, and to improve upon its biological activities. Novel nonsteroidal androgens, termed selective androgen receptor modulators, were developed to impart agonist activity in selective tissues. Drug preparations are used for the treatment of various androgen‐deficient diseases, for the therapy of diseases characterized by muscle wasting and protein catabolism, for postoperative adjuvant therapy, and for the treatment of certain hormone‐dependent cancers. The two major categories of androgen antagonists are the antiandrogens, which block interactions of androgens with the androgen receptor, and the inhibitors of androgen biosynthesis and metabolism. Such compounds have therapeutic potential in the treatment of acne, virilization in women, hyperplasia and neoplasia of the prostate, and baldness and male contraception.

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Metabolism of 17α-Methylandrostenediol and 17α-Methyltestosterone by the Rat Adrenal Glandin Vitro

Cited by 15 publications

References 7 publications

Some Studies on the Effect of Androgens on Adrenal Cortical Function of Rats

Some Studies on the Effect of Androgens on Adrenal Cortical Function of Rats

Peripheral serum corticosteroid concentrations in relation to the rat adrenal cortical circadian rhythm in androgen-induced hypertension.

Male Sex Hormones, Analogs, and Antagonists

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