Metabolism Dehydroepiandrosterone sulfate

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. 

The discovery of dehydroepiandrosterone sulfate secretion gave a new incentive to the whole study of conjugation, and it soon became evident that dehydroepiandrosterone sulfate could not only be biosynthesized from sulfo conjugated percursors along a direct biosynthetic pathway, but could also undergo further metabolism, with or without hydrolysis of the sulfate moiety (i.e., indirect or direct metabolism) and act as a privileged precursor of active steroids. 

Indirect and direct metabolism of dehydroepiandrosterone sulfate are combined in estrogen formation during pregnancy, since dehydroepiandrosterone sulfate is hydroxylated into 16a-hydroxydehydroepiandrosterone... 

After the first demonstration of a direct metabolism of a steroid conjugate [androstenediol sulfate =i dehydroepiandrosterone sulfate (Baulieu et ah, 1963)], showing that a 17j8-hydroxysteroid oxidoreductase can have a sulfo conjugate as a substrate, other enzymic transformations of dehydroepiandrosterone sulfate were reported (Fig. 4). Dehydroepiandrosterone sulfate can undergo 16o -hydroxylation to 16a-hydroxy-dehydroepiandrosterone sulfate which can be further hydroxylated into androstenetriol sulfate its direct 17-hydroxylated metabolite, androstene-... 

Testosterone sulfate does not seem to be hydrolyzed in the organism, but its direct metabolites have not been identified, as only 3.5% of the radioactivity was found in urine after radioactive testosterone sulfate administration. Unlike dehydroepiandrosterone sulfate, testosterone sulfate is not transformed by indirect metabolism into estrogens during pregnancy (Dray, 1963). 

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-... 

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. 

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). 

Fetal brain tissues also possess very active sulfokinases for dehydro-epjandro.steronc, and after incubation of tritium dehydroepiandrosterone with minced brain tissue from a human fetus in the twelfth week of gestation, 6% of the radioactive material consisted of ester sulfates (principally dehydroejnandrostcrone and androstenetriol sulfates). Moreover, the free fraction was largely metabolized to androstenediol, androstenetriol, and 16-ketoandrostenediol (Kiiapstein et al., 1968). 

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