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, 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 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.