Human hydroxysteroid sulfotransferase SULT2B1 pharmacogenomics: Gene sequence variation and functional genomics

Yuan Ji, Irene Moon, Jelena Zlatkovic, Oreste E. Salavaggione, Bianca A. Thomae, Bruce W. Eckloff, Eric D. Wieben, Daniel J. Schaid, Richard M. Weinshilboum

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The human hydroxysteroid sulfotransferase (SULT) 2B1 gene is a member of the cytosolic SULT gene superfamily. The two SULT2B1 isoforms, SULT2B1a and SULT2B1b, are encoded by a single gene as a result of alternative transcription initiation and alternative splicing. SULT2B1b catalyzes the sulfonation of 3β-hydroxysteroid hormones and cholesterol, whereas SULT2B1a preferentially catalyzes pregnenolone sulfonation. We used a genotype-to-phenotype approach to identify and characterize common sequence variation in SULT2B1. Specifically, we resequenced all exons, splice junctions, and ∼2.5 kb of the 5′-flanking regions (FRs) for each isoform using 60 DNA samples each from African-American and Caucasian-American subjects. We observed 100 polymorphisms, including four non-synonymous coding single nucleotide polymorphisms and one 6-base pair deletion - all within the "shared" region of the open reading frame. Functional genomic studies of the wild type (WT) and five variant allozymes for each isoform performed with a mammalian expression system showed that variant allozyme activities ranged from 64 to 88% of WT for SULT2B1a and from 76 to 98% for SULT2B1b. Relative levels of immunoreactive protein were similar to those for enzyme activity. Luciferase reporter gene constructs for 2.5 kb of the SULT2B1b 5′-FR displayed a cell line-dependent pattern of variation in activity. Finally, deletion of the proline-rich SULT2B1 carboxyl terminus resulted in intracellular protein aggregate formation and accelerated degradation of the truncated protein. These studies resulted in the identification of common SULT2B1 gene sequence variation, as well as insight into the effects of that variation on the function of this important steroid-metabolizing enzyme.

Original languageEnglish (US)
Pages (from-to)529-540
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number2
DOIs
StatePublished - Aug 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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