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Phenol Sulfotransferase Pharmacogenetics in Humans: Association of CommonSULT1A1Alleles with TS PST Phenotype

https://doi.org/10.1006/bbrc.1997.7466Get rights and content

Abstract

The phenol sulfotransferases (PSTs) catalyze the sulfation of both small planar phenols and phenolic monoamines. Three highly homologous PST genes,SULT1A1, SULT1A2,andSULT1A3,are known to exist in humans. The prototypic biochemical phenotype associated with the enzyme encoded bySULT1A1is the thermal stable (TS) sulfation of 4 μM 4-nitrophenol (TS PST activity). Biochemical pharmacogenetic studies have demonstrated that individual variation in both TS PST activity and thermal stability in humans are inherited. As a step toward understanding molecular mechanisms responsible for the genetic regulation of PSTs in humans, we report here commonSULT1A1nucleotide polymorphisms that are associated with phenotypic variation in both platelet TS PST activity and thermal stability. When 905 human subjects were phenotyped for platelet TS PST activity and thermal stability, activity varied more than 50-fold, and thermal stability varied over 10-fold. DNA was isolated from the blood of 33 of these subjects selected on the basis of “extreme” TS PST phenotypes: high activity and high thermal stability; low activity and low thermal stability; or low activity and high thermal stability. These 33 subjects were genotyped forSULT1A1by PCR amplification and sequencing of the entire open reading frame (ORF) as well as approximately 1 kb of intron DNA sequence. One common allele,SULT1A1*2,was uniformly associated with both very low TS PST activity and low thermal stability. The allele frequency ofSULT1A1*2in a randomly selected population sample of 150 Caucasian blood donors was 0.31 (31%), indicating that approximately 9% of this population would be homozygous for that allele.

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Supported in part by NIH Grants RO1 GM 28157 (R.M.W.) and RO1 GM 35720 (R.M.W.), by a supplement to RO1 GM 35720 supported by the Office of Research on Women's Health (R.M.W.), and by an NRSA (NIH) Individual Postdoctoral Fellowship (R.B.R.).

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