Dehydroepiandrosterone metabolism

FIGURE 52-6 Biosynthesis/metabolism of steroids in the CNS. The conversion of delta5P to dehydroepiandrosterone (DHA) is postulated but not demonstrated. D5P and DHA inhibit and 3oc,5oc-THP potentiates GABAa receptor function, as summarized in Figure 52-7. Solid arrows indicate demonstrated pathways dotted arrows indicate possible pathways. Metabolic inhibitors of enzymes are indicated by . (Redrawn from [12], with permission.)... 

WeEl-Engerer S, David JP, Sazdovitch V, Liere P, Schumacher M, et al. 2003. In vitro metabolism of dehydroepiandrosterone (DHEA) to 7alpha-hydroxy-DHEA and Delta5-androstene-3beta,17beta-diol in specific regions of the aging brain from Alzheimer s and non-de-mented patients. Brain Res 969 117-125. 

Deamination, metabolic, 72 Debrisoquin, 350 Dehydration, with DDQ, 168 Dehydroepiandrosterone, 158 Dehydrogenation... 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

Fluasterone is a stable adrenocortical steroid, a 16a-fluoro analogue of prasteron [dehydroepiandrosterone (DHEA)j. It is currently developed (phase II) for the treatment of metabolic syndrome (i.e. insulin resistance). Electrophilic... 

In all species, metabolism of testosterone leads to its biological deactivation. In sheep and cattle, this biological deactivation leads mainly to formation of epitestosterone, whereas in nonruminants it leads to androsterone, etiocholano-lone, and dehydroepiandrosterone (7-9). Residues of endogenous testosterone are usually highest in the kidneys of animals such as heifers witli a low testosterone production rate, and highest in fat of animals such as bulls, with a high production rate. 

SULT 1B1 functions in the sulfation of diverse endogenous substrates include cholesterol, dehydroepiandrosterone (DHEA), thyroid hormone, and dopamine. The enzyme also contributes to the metabolism of phenolic xenobiotics such as those containing 2-naphthol. It is highly expressed in the liver, colon, small intestine, and blood leukocytes. 

Tl. Taelman, R, Kaufman, J. M., and Janssens, X., Persistence of increased bone resorption and possible role of dehydroepiandrosterone as a bone metabolism determinant in osteoporotic women in late post-menopause. Maturitas 11, 65-73 (1989). 

The composition of the excreted urinary 17-ketosleroids also reveals a close similarity between the hormones of different origin the testis accounts for 30% while the adrenal cortex contributes the remaining 70% of the total urinary 17-ketosteroids [383]. Androsterone, ep a-androsterone, and 5/8-androsterone (etiocholanolone) are the main urinary metabolities of testosterone, and dehydroepiandrosterone is the major urinary 17-ketosteroid derived from the adrenal cortex. 

I) Consider three structurally similar Cis steroids —testosterone, an-drostenedione, and dehydroepiandrosterone. Each of these compounds is secreted into the blood stream by glands, and after provoking its biochemical effect, is metabolized and excreted. If the only source of the plasma pool were provided by the glandular secretion of the hormone, then the secretion rate would be used to calculate the plasma concentration. However, the picture in the case of the three Ci steroids is complicated by the fact that the three compounds are peripherally interconvertible. Since both glandular secretion and peripheral conversion of precursors contribute to the plasma pool, the production rate is used to... 

It has been shown that hormones are not exclusive products of the glands but are also formed in metabolizing organs. These hormones, however, contrary to the classical hormones, are not secreted into the blood. It has been established that testosterone formed in the liver from androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate does not enter the blood [305,323,388]. It has also been established that secreted and metabolically produced testosterone do not have the same metabolism [169, 311]. 

Formation of sulfates [328] is relatively reversible. This may be due to the fact that the metabolic clearance rate [318] of sulfates is relatively low [389] and their renal excretion inefficient [4]. The conversion of dehydroepiandrosterone sulfate in vivo to androsterone and etiocholanolone glucuronide was demonstrated by Lieberman and co-workers, who administered isotopically labeled dehydroepiandrosterone sulfate and isolated labeled androsterone and etiocholanolone from glucuronicase-hydrolyzed urine [303]. Since in another study by Lieberman [174], the transconjugation from dehydroepiandrosterone sulfate to dehydroepiandrosterone glucuronide without free dehydroepiandrosterone intermediate was declared to be improbable, in vivo equilibrium between dehydroepiandrosterone sulfate and dehydroepiandrosterone seems probable [303]. 

According to the classical view of metabolism the hormones are synthesized as free steroids in endocrine tissues and prepared for excretion in urine by peripheral metabolism and conjugation. This view had to be modified upon the isolation of dehydroepiandrosterone sulfate from adrenal tumor [307]. Thus dehydroepiandrosterone sulfate, a steroid conjugate, was shown to be secreted by the adrenal tissue. Isotopic methods also pointed in the same direction. Lieberman et al. [304], using... 

Metabolic studies carried out with isotopically labeled dehydroepi-androsterone sulfate [312] showed that this conjugated steroid may follow an indirect metabolic pathway initiated by the hydrolysis of the sulfate group. In the course of the metabolism the conjugated steroid thus becomes a free steroid first and the free steroid may undergo further metabolism. On the other hand, dehydroepiandrosterone sulfate may follow a direct metabolic pathway without a break of the ester group. 

Stimulation of the skin s metabolism the patient can apply a dehydroepiandrosterone (DHEA) cream if the extent of atrophy appears to makes this necessary. 

E.-E. Baulieu Dehydroepiandrosterone (DHEA) a fountain of youth Journal of Clinical Endocrinology and Metabolism 81, 3147 (1996). 

G. M. Meno-Tetang, Y. Y. Hon, S. Van Wart, and W. J. Jusko, Pharmacokinetic and pharmacodynamic interactions between dehydroepiandrosterone and prednisolone in the rat. Drug Metabol Drug Interact 15(l) 51-70 (1999). 

B24. Bolt5, E., Wiquist, N., and Diczfalusy, E., Metabolism of dehydroepiandrosterone and dehydroepiandrosterone sulphate by the human foetus at midpregnancy. Acta Endocrinol. 62, 583-597 (1966). 

Dehydroepiandrosterone (DHEA, (18)) is a major secretory product of the adrenal cortex [188] which ameliorates several metabolic abnormalities found in obese, insulin-resistant rodents. The first metabolic alteration was noted in mice carrying the viable yellow (genetic obesity) mutation [ 189] where a 0.2% dietary addition or oral administration (150-500 mg/kg, three times per week, 28 weeks) of DHEA reduced weight gain with no alteration in food consumption. Decreased accumulation of carcass triacylglycerol and decreased... 

Adrenocortical steroid hormones have a vast array of biological functions. Cortisol, the primary human glucocorticoid, regulates the inflammatory response (Newton and Holden, 2007), carbohydrate and lipid metabolism, and stress response (Kassel and Herrlich, 2007). Aldosterone regulates blood pressure by modulating fluid and electrolyte balance (Brizuela et ah, 2006 Foster, 2004). In the adrenal cortex, dehydroepiandrosterone (DHEA), dehy-droepiandrosterone sulfate (DHEA-S), and androstenedione are the androgens produced (Havelock et ah, 2004 Rainey et ah, 2002). 

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