Sulfotransferases in the bioactivation of xenobiotics
Section snippets
Early observations on the activation of carcinogens by sulfation
The first observations suggesting that bioactivation and covalent binding to macromolecules may be involved in the mechanism of a chemical carcinogen were published in 1947 [1]. By the late 1960s, it was evident that very many carcinogens are electrophiles or are metabolized to electrophiles [2]. A sulfuric acid ester, 2-acetylaminofluorene N-sulfate (N-sulfooxy-AAF), was the first electrophilic metabolite of a carcinogen to be discovered [3], [4]. In the subsequent years, the group of James
Physico-chemical and pharmacokinetic properties of sulfuric acid esters
The major physiological function of the conjugation of xenobiotics (or their metabolites) with endogenous anionic moieties is the formation of excretable products. The desired properties for the urinary and biliary excretion of metabolites are water solubility and a lack of passive penetration of cell membranes to avoid reabsorption.
Already in the last century, it was observed that some xenobiotics and endogenous compounds are excreted as sulfuric acid esters in the urine [12]. It is now known
Classification of sulfotransferases
Sulfotransferases transfer the sulfonate group from PAPS to a nucleophilic group of their substrates [13], [14], [15]; sporadically, the reverse reaction is also possible. In the mammalian organism, two classes of sulfotransferases can be distinguished. One class metabolizes macromolecular endogenous structures and comprises mainly membrane-bound forms localized in the Golgi apparatus. No xenobiotic-metabolizing activities have been reported for these forms. The other class of enzymes is
Tissue distribution and genetic polymorphisms of human SULTs
Human SULT1B1 [37], [38], 1C1 [39], [40], [41], 1C2 [41], 2B1a [42], 2B1b [42], and 4A1 [43], [44] have been detected only very recently; therefore, the knowledge of their function, substrate specificity, regulation, and genetic polymorphisms is minute. Their RNA and/or proteins have been detected in specific extrahepatic tissues, whereas their expression in adult liver appears to be low or not detectable. Kidney, stomach, and thyroid gland are the tissues showing the highest levels of hSULT1C1
Mutagenicity using recombinant bacteria and mammalian cell lines expressing individual SULT enzymes
Ames's S. typhimurium and Chinese hamster V79 cells, which are target cells of established mutagenicity tests, did not show sulfotransferase activity with any of the investigated substrates ([64], and U. Pabel, W. Meinl, and H.R. Glatt, unpublished results). We have expressed 29 different SULTs in S. typhimurium TA1538, and some forms also in strain TA100 and in V79 cells [65], [66]. In the recombinant bacterial strains, the expressed SULT amounts to approximately 1% of the total cytosolic
Macromolecular adducts in cell-free systems for the detection of SULT-mediated activation
Another approach that avoids the problem of membrane barriers in the detection of SULT-mediated activation is based on the formation of DNA or protein adducts in cell-free systems. A previous review [22] contains a list of compounds for which SULT-mediated activation has been demonstrated using this method. More recently, it was observed that rat hydroxysteroid sulfotransferase (rHSTa) enhances the formation of DNA adducts from (Z)-α-hydroxytamoxifen and (E)-α-hydroxytamoxifen [73]. The
Cyclic activation
Many reactive sulfuric acid esters are hydrolyzed spontaneously and, possibly, also through the action of sulfatases to the corresponding hydroxyl derivatives. Thus, these may be available for a new cycle of activation. Indeed, various chemically synthesized benzylic sulfuric acid esters (e.g. 1-SMP) showed enhanced mutagenicity in SULT-expressing Salmonella strains compared to control strains (H.R. Glatt, unpublished result). Moreover, incubation of [18O]-1-hydroxymethylpyrene in the presence
Relationships of SULT-mediated bioactivation with other activation pathways
As described above (Section 2) for 1-SMP, reactive sulfuric acid esters may react with numerous nucleophiles, including compounds of low molecular weight, which are common in the cell (e.g. amino acids, chloride ions, alcohols). Most of the reaction products formed from 1-SMP are still reactive and capable of forming the same DNA adducts as 1-SMP, although the reaction rates are lower in most cases [25]. Similar findings have been made with other benzylic sulfuric acid esters [25]. The
Detoxification by SULTs
While the subject of this article was SULT-mediated toxification, it has to be annotated that SULTs are beneficial in the metabolism of numerous xenobiotics. Many sulfates and sulfamates formed by SULTs are stable and have other physico-chemical properties which are favorable for their excretion.
SULTs rarely inactivate ultimate carcinogens and mutagens because these are normally electrophiles, whereas the SULTs transfer the sulfonate group to nucleophilic functional groups. However, SULTs may
Perspectives
It is now evident that O-sulfonation is a common toxification mechanism. Characteristic properties of this pathway are the possibility of cyclic reactivation and the formation of charged reactive species, which may not readily penetrate cell membranes unless this transmembrane transfer is mediated by transporters. Therefore a selective toxicity may be predicted in the cells in which sulfonation occurs and perhaps in other cells to which the conjugate is transferred in an active, vectorial
Acknowledgements
This work was supported financially by Deutsche Forschungsgemeinschaft (INK 26) and Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (grant 0311243).
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