Regulatory Effects of Divalent Metal Cations on Human Cytosolic Sulfotransferases

Abstract

Cytosolic sulfotransferases (STs), traditionally viewed as Phase II drug-metabolizing or detoxifying enzymes, are increasingly being implicated in the metabolism of endogenous biologically-active molecules. Except for studies on changes in their levels of expression and activity in the early stage of development in mammals, very little is known about how these enzymes are regulated. In this study, the regulatory effects of divalent metal cations on the activity of human cytosolic STs were quantitatively evaluated. Results obtained indicate that all nine human cytosolic STs examined are partially or completely inhibited/stimulated by the ten divalent metal cations tested at 10mM concentration. Compared with the other metal cations, the inhibitory or stimulatory effect of Mg²⁺ and Ca²⁺ on the activities of the human cytosolic STs appeared to be relatively smaller. Concentration-dependent effects of the divalent metal cations were further examined. The IC₅₀ or EC₅₀ values determined for different divalent metal cations were mostly above their normal physiological concentration ranges. In a few cases, however, IC₅₀ values close to the physiological concentrations of certain divalent metal cations were observed. Using the monoamine (M)-form phenol ST (PST) as a model, it was demonstrated that the K_m for dopamine changed only slightly with increasing concentrations of Cd²⁺, whereas the V_max was dramatically decreased.