Sulfation pharmacogenetics in humans

Abstract

Human tissues contain at least three well-characterized cytoplasmic sulfotransferase (ST) enzymes, thermostable (TS) and thermolabile (TL) forms of ST (PST) and dehydroepiandrosterone (DHEA) ST. Both forms of PST are expressed in an easily accessible human tissue, the blood platelet. The presence of PST in blood platelets made it possible to perform pharmacogenetic studies of these enzymes in humans. Those studied demonstrated that TS and TL PST activities in the human platelet are regulated by separate, common genetic polymorphisms. Furthermore, the platelet activity of TS, but not of TL PST is correlated with levels of this enzyme activity in other human tissues such as liver, jejunal mucosa and cerebral cortex. The pharmacogenetic strategy used to study TS and TL PST could not be applied to DHEA ST since that enzyme is not expressed in human blood elements. However, DHEA ST is expressed in the liver. When 94 samples of human hepatic biopsy tissue obtained during clinically-indicated surgery were studied, there was a 4.6-fold range of DHEA ST activity levels and a bimodal frequency distribution, with approximately 25% of the samples included in a ‘high activity’ subgroup. The presence of bimodality raised the possibility that human DHEA ST activity might also be regulated by a genetic polymorphism. Since a cDNA for human hepatic DHEA ST has been cloned, it will now be possible to study molecular genetic mechanisms that might be involved in the regulation of individual variation in DHEA ST activity in human hepatic tissue. Pharmacogenetic studies of ST enzymes are intended, ultimately, to determine the role of inheritance in the regulation of individual variation in the sulfate conjugation of drugs,, xenobiotics, neurotransmitters and hormones in humans.