Sulfotransferase (Sult) 1a1 Polymorphic Variants *1, *2, and *3 Are Associated with Altered Enzymatic Activity, Cellular Phenotype, and Protein Degradation.
From: Fox Chase Cancer Center, Philadelphia, PA, USA.
Molecular pharmacology
- Publish Date: Jun 2006
- ISSN: 0026-895X
- Volume: 69
- Issue: 6
- Pages: 2084-92
- Medium: Print
- Language: English
- Citation (JAMA): Nagar Swati, Walther Susan, Blanchard Rebecca L, et al. Sulfotransferase (Sult) 1a1 Polymorphic Variants *1, *2, and *3 Are Associated with Altered Enzymatic Activity, Cellular Phenotype, and Protein Degradation.. Mol. Pharmacol. Jun 2006;69:2084-92
Abstract
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, 17beta-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 V(max) estimates was *1 > *3 > *2; however, V(max)/K(m) 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.
Mesh Headings (Keywords): Animals, Arylsulfotransferase, Cells, Cultured, Estradiol, Estrogens, Catechol, Humans, Nitrophenols, Phenotype, Polymorphism, Genetic, Recombinant Proteins, Substrate Specificity
Check for Full Text / PubMed Unique Identifier (PMID): 16517757
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