Human sulfotransferase (SULT) 2A1 pharmacogenetics: Genotype to phenotype studies

Sulfate conjugation catalyzed by cytosolic SULTs plays an important role in the metabolism of many drugs, other xenobiotics and hormones. SULT2A1 catalyzes the sulfate conjugation of dehydroepiandrosterone (DHEA) as well as other steroids and is expressed in the liver, small intestine and adrenal cortex. We set out to determine whether there might be common, functionally significant single nucleotide polymorphisms (SNPs) in the human SULT2A1 gene. As a first step, we "resequenced" 60 DNA samples from African American and 60 samples from Caucasian subjects. All 6 exons as well as a portion of the 5′-fIanking region were sequenced with dye primer chemistry, for a total of approximately 0.6 Mb of sequence. We observed 15 novel SNPs, including 3 non-synonymous cSNPs detected only in African Americans. Expression constructs were created that included all of the nonsynonymous cSNPs observed and were expressed in COS-1 cells. After correction for transfection efficiency, there was a significant decrease in SULT2A1 activity for all three constructs that included SNPs as compared to that of the "wild type" sequence. These observations raise the possibility of ethnic-specific pharmacogenetic variation in SULT2A1-catalyzed sulfation.