Steroid hormone conjugates metabolism

Conjugations can also be brought about by sulfotransferases (SULTs) and glutathi-one-S-transferases (GSTs), both of which exist in a number of isoenzymic forms. Amines and alcohols are sulfate acceptors and SULTs are important in steroid hormone and catecholamine metabolism and like the UGTs require the sulfate to be activated prior to its incorporation into the target molecule (Figure 6.32). In this case, sulfate is activated at the expense of two molecules of ATP to form the final sulfate carrier PAPS O -phosphoadenosine-S -phosphosulfate). 

The steroid hormones are mainly inactivated in the liver, where they are either reduced or further hydroxylated and then conjugated with glucuronic acid or sulfate for excretion (see p. 316). The reduction reactions attack 0X0 groups and the double bond in ring A. A combination of several inactivation reactions gives rise to many different steroid metabolites that have lost most of their hormonal activity. Finally, they are excreted with the urine and also partly via the bile. Evidence of steroids and steroid metabolites in the urine is used to investigate the hormone metabolism. 

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-... 

Approximately 50% of a dose of mestranol is de-methylated to form ethinyl estradiol. Ethinyl estradiol also can be deethinylated. Subsequently, the metabolism of these two synthetic estrogens proceeds by means of the same pathways as the natural steroid hormones. The principal metabolites of mestranol and ethinyl estradiol are hydroxylated derivatives that are conjugated with either glucuronic acid or sulfate. The synthetic steroid estrogens, in contrast to the natural estrogens, are excreted primarily in the feces. 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

The liver metabolizes drugs, other foreign chemical compounds (xenobiotics), and certain endogenous substances (e.g., steroid hormones, bilirubin) by a variety of pathways. They include hepatic microsomal-mediated oxidative reactions, reductive and hydrolytic reactions (phase I), and conjugation (synthetic) reactions with various endogenous substances (phase II) [58,59] j metabolic reactions occur ubiqui-... 

A bibliography of steroid conjugates as well as a treatise on the metabolism of steroid hormones have been published. The abstracts of papers presented at the Second International Congress of Hormonal Steroids are available. ... 

The conjugation and inactivation pathways are similar to those used by the hver to inactivate many of its own metabolic waste products. These pathways are intimately related to the biosynthetic cascades that exist in the liver. The liver can synthesize the precursors that are required for conjugation and inactivation reactions from other compounds. For example, sulfation is used by the liver to clear steroid hormones from the circulation. The sulfate used for this purpose can be obtained from the degradation of cysteine or methionine. 

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