Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation.
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.
Nagar
Swati
S
Fox Chase Cancer Center, Philadelphia, PA, USA.
Walther
Susan
S
Blanchard
Rebecca L
RL
D000077584:2-Methoxyestradiol; D000818:Animals; D015239:Arylsulfotransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry; D002393:Estrogens, Catechol / Q000737:chemistry; D006801:Humans; D009596:Nitrophenols / Q000737:chemistry; D010641:Phenotype; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D002393:Estrogens, Catechol; D009596:Nitrophenols; D011994:Recombinant Proteins; D004958:Estradiol; D000077584:2-Methoxyestradiol; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C024836:4-nitrophenol