Sulfate conjugation is an important pathway in the metabolism of many drugs, xenobiotic compounds, hormones and neurotransmitters. During the past decade and a half, the applicant's laboratory has systematically explored the biochemistry, molecular biology and regulation of the family of cytosolic enzymes that catalyzes sulfate conjugation in humans. Special emphasis has been placed on the role of inheritance in the regulation of these enzyme activities, i.e., on pharmacogenetics. It is now known that human tissues contain at least four cytosolic sulfotransferase (ST) enzymes, thermolabile (TL) and thermostable (TS) forms of phenol ST (PST), an hydroxysteroid ST most often referred to as dehydroepiandrosterone (DHEA) ST and an estrogen ST (EST). We have already described and characterized genetic polymorphisms in humans for TL and TS PST and have developed evidence which also raises that possibility for DHEA ST. The present proposal is devoted to studies of the molecular pharmacogenetics of ST enzymes in humans. The applicant's laboratory has cloned cDNAs for DHEA ST, TL PST and EST in humans and has cloned and characterized the gene for DHEA ST. The cDNA and gene for the remaining known human ST, TS PST, have been cloned in another laboratory. We now propose to extend our studies of the pharmacogenetics of sulfation in humans to include cloning of the gene or genes for the two remaining known human cytosolic ST enzymes, TL PST and EST. We will then attempt to determine the molecular basis of the genetic polymorphisms for TL PST and TS PST that we discovered and to explore the possibility -- a possibility raised by our own studies -- that a genetic polymorphism might also regulate the activity of DHEA ST in human liver. We will then develop molecular techniques for use in studying the regulation, including pharmacogenetic regulation, of EST in human tissue. In those cases in which we determine the molecular basis of genetic polymorphisms, DNA-based tests will be developed to explore the role of inherited variations in ST enzyme activities in individual differences in response to drugs and endogenous compounds. The results of the proposed experiments will serve to increase our understanding of molecular mechanisms responsible for the pharmacogenetic regulation of enzymes that catalyze the sulfate conjugation of drugs, xenobiotic compounds, hormones and neurotransmitters in humans. They will also help make it possible to predict individual variations in the biotransformation of compounds metabolized by sulfation.
Showing the most recent 10 out of 86 publications
