Sultdependent Activation And Inactivation Chemical Background

SULTs transfer the sulfo/sulfuryl group from the cofactor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to nucleophilic groups of their substrates (Glatt, 2002). The resulting sulfate, thiosulfate, and sulfamate groups are electron-withdrawing and are therefore good leaving groups in certain chemical linkages. A trivial example is H2SO4, which is a strong bivalent acid. Likewise, the sulfate group is readily cleaved off spontaneously in sulfuric acid esters of many benzylic alcohols, allylic alcohols, aromatic hydroxylamines, and aromatic hydroxamic acids as the resulting carbonium or carbonium/nitrenium ions are resonance-stabilized. Other mechanisms, such as inductive effects, may also facilitate heterolytic cleavage. Reactive sulfuric acid esters will react, usually via an SN1 mechanism, with cellular nucleophiles, such as the DNA, but also with water, regenerating the metabolic precursor of the sulfocon-jugate (Landsiedel et al., 1996), as illustrated in Figure 13.1 for 1-hydroxymeth-ylpyrene (1; underlined bold numbers indicate structural formulas presented in numerical order in Figure 13.1, Figure 13.2, Figure 13.5, Figure 13.6, and Figure 13.10).

Most ultimate mutagens are electrophiles, which find reaction partners in the numerous nucleophilic sites present in DNA (and other macromolecules; Miller, 1970). The sulfo acceptor sites of the substrates of SULTs are nucleophilic and, therefore, are not reactive toward DNA, which lacks significant electrophilic sites. In this regard, SULTs are not suited to detoxify ultimate mutagens. However, SULTs may compete with other enzymatic and spontaneous (e.g., autoxidative) reaction pathways, including those generating electrophilic products, for the same substrates. Therefore, sulfoconjugation can be beneficial via the sequestration of potential proximate toxicants. In fact, this situation is rather common. With various classes of chemicals, for example aromatic amines, sulfoconjugation is involved in both the activation as well as the sequestration of progenotoxicants (Figure 13.2).

Thyroid Hormone Cell Background

figure 13.1 Metabolic pathways of 1-hydroxymethylpyrene (1) leading to the formation of DNA adducts. The conversion of 1 to 1-sulfooxymethylpyrene (2) is catalyzed by SULTs. All other reactions occur spontaneously in the presence of the appropriate reactants (H2O, Cl-, and DNA, respectively). Cl- represents here numerous small nucleophilic molecules that may lead to the formation of secondary reactive species (such as 1-chloromethylpyrene, 4; Landsiedel et al., 1996). In addition to the desoxyguanosine adduct (5), several minor DNA adducts are formed.

figure 13.1 Metabolic pathways of 1-hydroxymethylpyrene (1) leading to the formation of DNA adducts. The conversion of 1 to 1-sulfooxymethylpyrene (2) is catalyzed by SULTs. All other reactions occur spontaneously in the presence of the appropriate reactants (H2O, Cl-, and DNA, respectively). Cl- represents here numerous small nucleophilic molecules that may lead to the formation of secondary reactive species (such as 1-chloromethylpyrene, 4; Landsiedel et al., 1996). In addition to the desoxyguanosine adduct (5), several minor DNA adducts are formed.

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