Ontogeny of the Phase II cytosolic sulfotransferases and adverse drug reactions

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DESCRIPTION (provided by applicant): A variety of pediatric drugs are currently in use for treating infants/children afflicted with different diseases/disorders. These drugs, while serving their therapeutic purposes, may exert adverse effects. Two important questions therefore are: i) whether the developing infants/children are equipped with mechanism(s) for protection against the adverse effects of pediatric drugs, and ii) how the emergence of such protection mechanism(s), during the infant/child development, may help alleviate these adverse effects. In humans and other vertebrates, sulfation as mediated by the SULTs is known to play a major role in the detoxification of xenobiotics. Of particular interest in this proposed research is the role that sulfation may play in influencing the susceptibility of the developing infants/children t the adverse effects of pediatric drugs. In our recent studies using the zebrafish as a model, we demonstrated that different SULTs exhibited distinct patterns of expression at different stages during embryogenesis on to larval development. Moreover, like human SULTs, zebrafish SULTs displayed differential sulfating activities toward a number of drugs tested. In view of the crucial role of these enzymes in the detoxification of xenobiotics, we hypothesize that the susceptibility of the developing infants/children, and likewise zebrafish embryos/larvae, to any potential adverse effects of drugs may be dependent on the ontogeny and tissue/organ-specific expression of relevant drug-sulfating SULTs. To verify this hypothesis, selected pediatric drugs that are commonly used for treating cough/cold and allergy/asthma symptoms in infants/children will be tested. These drugs, especially when improperly administered, may cause adverse effects including death in extreme cases. The proposed research will address three issues that are pertinent to the above-mentioned hypothesis, namely the drug- sulfating capacity of the SULTs, their ontogeny and tissue/organ distribution, and the involvement of relevant drug-sulfating SULTs in protection against the adverse effects of drugs. The specific aims are: 1. To analyze the sulfating activity of our established repertoires of human and zebrafish SULTs toward selected pediatric drugs, and to clarify the ontogeny and tissue/organ-specific expression of relevant human and zebrafish drug-sulfating SULTs; and 2. To verify the involvement of relevant drug-sulfating SULTs in protection against the adverse effects of selected pediatric drugs during zebrafish development. Successful completion of this project will reveal how the ontogeny and tissue/organ-specific expression of relevant drug-sulfating SULTs may influence the susceptibility to any potential adverse effects of the tested pediatric drugs during development. With better understanding about the ontogeny of human drug-sulfating SULTs and their substrate specificity and catalytic efficiency, the information obtained may eventually become useful in helping to choose particular types and doses of the pediatric drugs for different age groups of infants/ children, thereby alleviating potential adverse effects that may occur at different stages during development.