Sulfotransferases EC 282

Sulfotransferases (SULTs)55 catalyze the transfer of a sulfonyl group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to nucleophilic substituents of their substrates, analogous to the UGTs. Accordingly, SULTs are often detoxifying enzymes for the same reasons discussed above for the UGTs. On the other hand, sulfoconjugation is in a predictable fashion also an important toxification mechanism for several types of precarcinogens.55,56 Aromatic hydroxylamines, metabolically produced from aromatic amines by CYP, are metabolized by SULT to aromatic N-O-sulfate esters, which heterolytically decompose to the sulfate anion and to the genotoxic nitrenium ions. Sulfation of benzylic alcohols leads to the formation of reactive carbenium ions after cleaving off the sulfate group. Thus, mice with an inherited deficiency in the synthesis of the cofactor required for SULTactivity, PAPS, are less prone to develop liver cancer when treated with the hepatocarcinogen 1'-hydroxysafrol.1

SULTs have a substrate spectrum similar to that of the UGTs, except they do not conjugate carboxylic acids. Generally, SULTs have a lower Km than UGTs. Hence, an important detoxification function of SULT is the efficient conjugation of low amounts of xenobiotics. They have a high affinity but only limited capacity for their substrates. The concentrations of the respective cosubstrates are in line with this: the PAPS concentration in the human liver is about 50 mM and UDPGA is present at an approximately 10-fold higher concentration. Thus, in general, drugs are preferentially sulfated at low concentrations and preferentially glucuronidated at high concentrations. When interpreting results from toxicity testing it is important to note that if for a given drug one of these pathways represents a detoxification and the other a toxification, low environmental or moderate therapeutic doses can lead to the opposite effect to the high concentrations used in toxicity tests.1

The SULT families55 are described elsewhere in this book (see 5.06 Principles of Drug Metabolism 2: Hydrolysis and Conjugation Reactions).

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