Dehydroepiandrosterone conjugates

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 2A and 2B sulfotransferase subfamily members sulfate the 3P-hydroxyl group of a variety of steroid hormones. Dehydroepiandrosterone (DHEA) is the prototypical substrate for the SULT 2 enzymes. However, other hydroxysteroids such as testosterone and its phase I hydroxylated derivatives are substrates for these enzymes. The SULT 2 sulfotransferases also are responsible for the sulfate conjugation of a variety of alcohols and xenobiotics that have undergone phase I hydro-xylation, including the polycyclic aromatic hydrocarbons (PAHs). The SULT 2 enzymes exhibit different patterns of tissue expression. SULT 2A1 is expressed primarily in the adrenal cortex, brain, liver, and intestine, while SULT 2B1 is expressed in the prostate, placenta, and trachea. 

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. 

Neutral corticosteroids are prone to the formation of acid adducts [M+RCOO] in negative-ion mode [20-21]. Abundant acetate adducts are observed for steroids with a relatively acidic hydroxyl group [22]. In negative-ion TSP ionization, Kim et al. [23] observed more abundant acid adducts with decreasing pK, of the acid. Marwah et al. [24] showed signal enhancement for a variety of steroids like dehydroepiandrosterone (DHEA) and related compounds due to the addition of low concentration of acid, i.e., typically 1-5 mmol/1 formic acid, 1-8 mmol/1 acetic acid, or 0.05-0.15 mmol/1 trifluoroacetic acid, while higher acid concentrations were found to compromise the response. Formic acid was the best choice for the neutral steroids, while acetic acid is preferred for sulfate conjugates. Post-column addition of 10 nmol/1 silver nitrate resulted in a ten-fold increase in the response for androst-5-ene-3p,17P-diol. [M+Ag] is observed instead of [M+H-HjO] [24]. 

Rosenfield RL. A competitive protein binding method for the measurement of unconjugated and sulfate-conjugated dehydroepiandrosterone in peripheral plasma. Steroids 1971 17 689-96. 

In the third example, dehydroepiandrosterone is widely used for standardizing and for checking the performance of the Zimmermann reaction, which forms the final step in many methods of steroid estimation. There is, however, no suitable standard preparation including the commoner urinary steroids and their metabolites which can be carried through all the previous stages of analysis, and the only satisfactory form of standard material that includes the naturally occurring conjugates of the main steroids and their metabolites is urine collected from normal individuals or from patients treated with cortisol. 

The prototypical 17-alkylandrogen, 17- methyltestosterone, is prepared from dehydroepiandrosterone (DHEA 1-5) in two steps. Reaction of DHEA with an excess of methylmagnesium bromide gives the corresponding 17-methyl derivative (13-1) (Scheme 5.13). Oppenauer oxidation then converts the hydroxyl at C3 to a carbonyl group the olefin shifts into conjugation in the process to give mestanolone (13-2). 

An effective antiserum for dehydroepiandrosterone 3-sulphate has been obtained by use of the 17-hydrazone as hapten, coupled to BSA. 3a,5p Tetrahydroaldosterone (22), the main urinary metabolite of aldosterone, is efficiently bound by an antiserum induced by the conjugate of BSA with the 3-carboxymethyloxime of aldosterone 18,21-diacetate. Haptens for RIA of cortisone and cortisol have been prepared by the introduction of 7a- and 7/3-carboxymethyl substituents (23) through a malonic ester condensation with the 7-bromo-derivative (24). ... 

Sulfate conjugates dehydroepiandrosterone sulfate, estrone-3-sulfate Others cholesterol, estradiol Characteristics Phospholipids... 

The bulk of dehydroxyepiandrosterone is converted to sulfate and excreted. However, the conjugation reaction is reversible, and consequently labeled androster-one is in the urine after injection of labeled dehydroxyepiandrosterone sulfate. Adrenal tissues can convert dehydroepiandrosterone to androstenedione or testosterone. 

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. 

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