Interactions between dietary chemicals and human sulfotransferases-molecular mechanisms and clinical significance.
Sulfation plays a major role in the detoxication of xenobiotics as well as in modulating the biological activity of numerous important endogenous chemicals. In contrast to this "chemical defense" function, sulfation is also a key step in the bioactivation of a host of pro-mutagens and pro-carcinogens. These reactions are catalyzed by an expanding family of sulfotransferase (SULT) enzymes, which transfer a sulfuryl moiety from the universal donor 3'-phosphoadenosine 5'-phosphosulfate. Here, we discuss current knowledge of the human sulfotransferase enzyme family, of which at least 11 members have been identified to date, including regulation of expression by endogenous compounds and xenobiotics as well as the molecular basis of polymorphisms in members of the SULT1A (phenol sulfotransferase) family. We also present new data on the inhibition of SULT1A enzymes by dietary chemicals, showing that compounds to which we are exposed regularly, such as epigallocatechin gallate and epicatechin gallate are extremely potent inhibitors of phenol sulfotransferases (K(i) in the nanomolar range for SULT1A1). We found that the mechanism of inhibition by these chemicals varied depending on the individual isoform involved, showing uncompetitive inhibition of SULT1A1 whereas with SULT1A2 and -1A3 they demonstrated mixed type inhibition. Thus, genetic-environmental interactions may play an important role in modulating sulfotransferase activity and in determining individual response to chemicals metabolized by these important enzymes.
Coughtrie
M W
MW
Department of Molecular and Cellular Pathology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom. m.w.h.coughtrie@dundee.ac.uk
Johnston
L E
LE
D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000494:pharmacology; D004032:Diet; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009153:Mutagens / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D002273:Carcinogens; D009153:Mutagens; D011994:Recombinant Proteins; D015238:Sulfotransferases