Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation
| Autor: | Swati Nagar, Rebecca L. Blanchard, Susan E Walther |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Sulfotransferase
medicine.medical_treatment Protein degradation law.invention Steroid Substrate Specificity Nitrophenols Sulfation Ubiquitin law medicine Animals Humans Cells Cultured Pharmacology chemistry.chemical_classification Polymorphism Genetic biology Estradiol Arylsulfotransferase Estrogens Catechol Recombinant Proteins 2-Methoxyestradiol Enzyme Phenotype chemistry Biochemistry biology.protein Recombinant DNA Molecular Medicine Intracellular |
| Zdroj: | Molecular pharmacology. 69(6) |
| ISSN: | 0026-895X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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