Substrates of sulfotransferases

Sulfotransferases act on a very large variety of compounds bearing a phenolic, alcoholic, hydroxylamino, or amino function. These substrates include endogenous compounds (e.g., catecholamines, steroids, and bile acids), dietary constituents (e.g., flavonoids), procarcinogens (e.g., benzylic alcohols and heterocyclic aromatic amines, see below), and drugs.

Phenols form stable aryl sulfate esters (Figure 12a). The reaction is usually of high affinity (i.e., rapid), but the limited availability of PAPS restricts the amounts of conjugate being produced. Given that phenols are also substrates of glucuronyltransferases (see Section 5.06.3.4), a competition for the two reactions is frequently seen, with the high-affinity but low-capacity sulfation predominating at lower doses, and the lower affinity but higher capacity glucuronidation predominating at higher doses. This typical situation is aptly exemplified by contrasting the relative sulfation and glucuronidation of the high-dose drug paracetamol (30, Figure 13), whose major metabolite is an aryl glucuronide, with those of the low-dose drug troglitazone (31), whose major metabolite in human plasma is the aryl sulfate rather than the aryl glucuronide.61 Sulfation, like glucuronidation (discussed in Section 5.06.3.4), is also a route of significance in the conjugation of phenols generated as phase I metabolites of aromatic drugs, e.g., 4-hydroxypropranol.62

Quantitative structure-activity relationship (QSAR) investigations based on sulfation rates obtained with recombinant human SULT enzymes have uncovered some valuable trends for SULT1A3.46 Factors favoring the rate of sulfation were, for example, lipophilicity and a basic amino group or a zwitterionic nature of the compound; unfavorable factors included a carboxy group and the number of H-bond acceptor groups.

The sulfoconjugation of alcohols (Figure 12a) leads to metabolites of different stabilities. Endogenous hydroxysteroids (i.e., cyclic secondary alcohols) form relatively stable sulfates, while some secondary alcohol metabolites of allylbenzenes (e.g., safrole and estragole) form highly genotoxic carbocations.63 Primary alcohols, e.g., methanol and ethanol, can also form sulfates whose alkylating capacity is well known and results from the heterolytic cleavage of the C-O bond. Similarly, polycyclic hydroxymethylarenes yield reactive sulfates believed to account for their mutagenicity and carcinogenicity.52 The reaction is not without medicinal relevance, since, for example, the sulfate ester (32, Figure 13) of a-hydroxytamoxifen, a well-known metabolite of the antiestrogen tamoxifen, has been

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