• DOI:10.1124/mol.105.019240
• Corpus ID: 12640813

Sulfotransferase (SULT) 1A1 Polymorphic Variants *1, *2, and *3 Are Associated with Altered Enzymatic Activity, Cellular Phenotype, and Protein Degradation

@article{Nagar2006Sulfotransferase1,
  title={Sulfotransferase (SULT) 1A1 Polymorphic Variants *1, *2, and *3 Are Associated with Altered Enzymatic Activity, Cellular Phenotype, and Protein Degradation},
  author={Swati Nagar and Susan E. Walther and Rebecca L. Blanchard},
  journal={Molecular Pharmacology},
  year={2006},
  volume={69},
  pages={2084 - 2092}
}

• S. Nagar, S. Walther, R. Blanchard
• Published 1 June 2006
• Biology
• Molecular Pharmacology

The superfamily of sulfotransferase (SULT) enzymes catalyzes the sulfate conjugation of several pharmacologically important endo- and xenobiotics. SULT1A1 catalyzes the sulfation of small planar phenols such as neurotransmitters, steroid hormones, acetaminophen, and p-nitrophenol (PNP). Genetic polymorphisms in the human SULT1A1 gene define three alleles, SULT1A1*1, *2, and *3. The enzyme activities of the SULT1A1 allozymes were studied with a variety of substrates, including PNP, 17β-estradiol, 2-methoxyestradiol, catecholestrogens, the antiestrogen 4-hydroxytamoxifen (OHT), and dietary flavonoids. Using purified recombinant SULT1A1 protein, marked differences in *1, *2, and *3 activity toward every substrate studied were noted. Substrate inhibition was observed for most substrates. In general, the trend in Vmax estimates was *1 > *3 > *2; however, Vmax/Km estimate trends varied with substrate. In MCF-7 cells stably expressing either SULT1A1*1 or *2, the antiestrogenic response to OHT was found to be allele-specific: the cells expressing *2 exhibited a better antiproliferative response. The intracellular stability of the *1 and *2 allozymes was examined in insect as well as mammalian cells. The SULT1A1*2 protein had a shorter half-life than the *1 protein. In addition, the *2 protein was ubiquitinated to a greater extent than *1, suggesting increased degradation via a proteasome pathway. The results of this study suggest marked differences in activity of polymorphic SULT1A1 variants, including SULT1A1*3, toward a variety of substrates. These differences are potentially critical for understanding interindividual variability in drug response and toxicity, as well as cancer risk and incidence.