Cytosolic sulfotransferases (STs) catalyze the sulfonation of both endogenous and xenobiotic agents, and this usually results in the bioactivation and excretion of sulfoconjugates. Seven members of the human ST gene superfamily have been cloned to date. Three of the genes cloned and mapped by the applicant and his coworkers encode the phenol sulfotransferase gene loci, STP1, STP2, and STM. The preferred substrates for STP1, STP2, and STM, and the SULT1B2 gene products are phenolic drugs, thyroid hormones, and catecholamines. Two other loci, STE and STD, encode gene products capable of sulfating steroids, and the biochemical activity of SULT1C1 is unknown. Biochemical and immunohistochemical studies have indicated the presence of STs in mammalian skin and other epithelia. However, very little is currently known in detail about the regulation and patterns of expression of the ST gene superfamily in normal and transformed human epithelial tissues and cell lines. Several of these genes have been implicated in the formation of cholesterol sulfate and minoxidil sulfate, which regulate differentiation of skin keratinocytes and minoxidil-induced hairgrowth, respectively. As such, the superfamily is of critical importance in the differentiation of human epithelia, and is likely to be involved in the bioactivation or bioinactivation of xenobiotic toxic chemicals, mutagens, procarcinogens, and drugs within epithelia and carcinomas. Therefore, we propose to examine this gene superfamily vis-à-vis their roles in regulation of epithelial biology.
The Specific Aims i nclude: (1) to determine the patterns of expression of the human cytosolic ST gene superfamily and the X-linked arylsulfatase genes in normal epithelia and cell lines; (2) to determine the patterns of expression of the human ST and arylsulfatase genes in epithelial tumors (carcinomas) and transformed cell lines; (3) to identify the epithelial-specific regulatory domains of the promoter sequences for each of the epithelial ST genes; (4) to demonstrate that the STE gene is responsible for the formation of cholesterol sulfate and regulation of differentiation in skin keratinocytes; and (5) to demonstrate that the STP1 and/or STM genes are responsible for the formation of minoxidil sulfate in keratinocytes of the outer root sheath of hair follicles and interfollicular epidermis. The anticipated results will provide valuable insights into the roles of the human ST gene superfamily in the metabolism and bioavailability of drugs and endogenous compounds in human epithelia and cancers.
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