Alcohols sulfate conjugation

Many drugs and metabolites are metabolized by conjugation with sulfate or glucuronic acid as described in Chapter 7. Sulfate conjugates can be hydrolyzed back to the alcohol or phenol. Glucuronide conjugates can involve a wider variety of functional groups and... 

In a general sense, the kinetics and metabolism of toluene in humans, rats and mice are very similar the hippurate is in all cases by far the major metabolite, while in all species the ortho- and / ora-cresols are minor metabolites. To what extent formation of a potentially reactive sulfate conjugate of benzyl alcohol occurs (van Doom et al., 1980 Chidgley et al., 1986) is uncertain, mainly because mercapturates formed from toluene have not been characterized. Similarly, whether the covalent binding observed in rat liver microsomes has any toxicological relevance is uncertain. 

Sulfate conjugation Phosphoadenosyl phosphosulfate Sulfotransferase (cytosol) Phenols, alcohols, aromatic amines Estrone, aniline, phenol, 3-hydroxy-coumarin, acetaminophen, methyldopa... 

The types of species that form sulfate conjugates are alcohols, phenols, and aryl amines, as shown by the examples in Figure 7.11. 

TABLE 12.3. Examples of Sulfate Conjugation to Alcohols, Phenols, and Aromatic Amines... 

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. 

The lactam derivative dibenz[h/]l 4-oxazepin-ll-(lOH)-one is a primary metabolic product of metabolism and a direct precursor of the urinary hydroxylated metabolites. In rats, the lactam, a dihydro-CR metabolite, an amino alcohol of CR, and an arene oxide are metabolites in CR degradation. In the rat, the major mechanism for elimination is sulfate conjugation and biliary excretion to a limited extent. Phase I metabolism by microsomal mixed fimction oxidases involves reduction of CR to the amino alcohol, oxidation to form the lactam ring, and hydroxylation to form the hydroxylactams. Phase II conjugation reactions sulfate the hydroxylactam intermediates for renal elimination. Amino alcohol intermediates are conjugated with glucuro-nide for biliary secretion. 

The activities of the conjugating enzymes (transferases) are also genetically determined, but these activities can be induced by various environmental factors such as alcohol, coffee, oral contraceptives, diet, and tobacco as well (Mucklow et al. 1980). An example of interethnic differences in conjugation can be seen in the clearance of acetaminophen (85%-90% excreted after glucuronide or sulfate conjugation), which is 20% slower in Asians than in Europeans. 

Figure 8. Example of a sulfate conjugate (4-nitrobenzyl alcohol sulfate) serving as a substrate for glutathione conjugation. Values are percent of indicated metabolite formed by rat hepatocytes (15).

Ethanol has been shown to block the metabolism of 2-butoxyethanol to 2-butoxyacetic acid through competitive inhibition of alcohol dehydrogenase (Romer et al. 1985). Administration of ethanol after 2-butoxyethanol exposure can be used to control the production of toxic metabolites and to promote conjugation of the parent compound to nontoxic products of elimination such as the glucuronide and sulfate conjugates. This approach has been recommended for clinical therapy for 2-butoxyethanol poisoning (Buckley et al. 1993). 

Sulfate conjugation PAP-sulfate Sulfotransferase (cytosol) Phenols alcohols aromatic amines... 

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