Sulfation endogenous substrates

Sulfotransferases catalyze the transfer of sulfate from PAPS to wide-range xenobiotics that possess hydroxyl groups. Steroid alcohols are among the endogenous substrates. The sulfotransferases exist in different forms. 

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-... 

Glutathione and sulfatation conjugations are important pathways for generally detoxifying endogenous substrates and xenobiotics (Commanndeur et al. 1995). However, some produced metabolites (ie mercapturic acids, O-sulfo conjugates) are toxic by different mechanisms, often by reaction with DNA and other cellular nucleophiles. 

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. 

Alcohols, phenols, hydroxylamines, and amines can be sulfated, as can endogenous substrates such as steroids, polysaccharides, and biogenic amines. Sulfation can lead to metabolites that are more toxic than their precursors (Fig. 6). 

Reactions of biotransformation of xenobiotics are usually divided into Phase I and Phase II reactions. In Phase I reactions a polar group, such as hydroxyl (-OH), carboxyl (-COOH), thiol (-SH) and amino (-NH2) group, is introduced into the molecule through the reactions of oxidation, reduction and hydrolysis. Metabolites formed can be more toxic than parent compounds (i.e. paraoxon compared to parathion), but some other nontoxic metabolites can be formed as well. In Phase II reactions polar metabolites are conjugated with endogenous substrates such as glucuronides, sulfates, acetates and amino acids, which form hydrosoluble products that can be readily excreted in urine. However, in the case of OPC it is acceptable to divide reactions of biotransformation to activation and detoxication processes. In these metabolic processes significant role have diflerent enzyme... 

Another enzyme in this class is steryl sulfatase (steroid sulfatase, steryl-sulfate hydrolase, EC 3.1.6.2). The typical substrate of this enzyme is the endogenous metabolite 3/3-hydroxyandrost-5-en-17-one 3-sulfate, but the enzyme also hydrolyzes some related steryl sulfates. 

A number of enzymes known as sulfuric ester hydrolases (EC 3.1.6) are able to hydrolyze sulfuric acid esters. They comprise arylsulfatase (sulfatase, EC 3.1.6.1), steryl-sulfatase (steroid sulfatase, steryl-sulfate sulfohydrolase, arylsulfatase C, EC 3.1.6.2), choline-sulfatase (choline-sulfate sulfohydrolase, EC 3.1.6.6), and monomethyl-sulfatase (EC 3.1.6.16). Whereas mono-methyl-sulfatase is highly specific and does not act on higher homologues, arylsulfatase has a broad substrate specificity and is of particular significance in the hydrolysis of sulfate conjugates of phenols, be they endogenous compounds, drugs, or their metabolites [167-169],... 

The formation of sulfate esters is a major route of conjugation for various types of hydroxyl group, and may also occur with amino groups. Thus, substrates include aliphatic alcohols, phenols, aromatic amines, and also endogenous compounds such as steroids and carbohydrates (Figs. 4.56 and 4.57). 

The hepatic cytochrome P-450 system exhibits a broad substrate specificity, and many lipophilic compounds including drugs, chemicals, and endogenous metabolites are oxidized by it (Table 14-8). The hydroxylated compounds are converted to more polar metabolites by conjugation with glucuronate, sulfate, amino acids, or acetate that is catalyzed by appropriate transferases. The polar metabolites are excreted by either the biliary-intestinal or the renal system. 

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